Inom humanmedicinen görs en relativt enkel indelning av diabetes i typ 1- och typ 2. Vid typ 1-diabetes saknar pankreas helt eller delvis förmågan att producera insulin. När det gäller typ 2 är det istället insulinresistens som orsakar sjukdom (Alberti & Zimmet, 1998). Hos hund är indelningen inte fullt så enkel och det finns ingen vedertagen internationell klassificering. Catchpole et al (2005) föreslår en indelning i IDD och IRD, men Fall (2009) menar att det är lämpligare att klassificera efter orsaken till att diabetes uppstått, vilket resulterar i en rad olika klasser. Det är svårt att säga vilken klassificering som är mest lämplig för hund. Fördelen med att dela in i IDD och IRD är att det är förhållandevis enkelt med bara två klasser att hålla reda på. Men som Fall (2009) påpekar finns vissa brister med denna klassificering. Nackdelarna är att många fall är idiopatiska och för dessa finns ingen bra klassificering, men också att många hundar tycks växla från IRD till IDD på grund av glukotoxicitet. Dessutom menar Fall (2009) att missförstånd kan uppstå i kommunikation med läkare som är vana att klassificera diabetes som typ 1 eller typ 2. Detta då klasserna IDD och IRD påminner om typ 1 och typ 2, men de är inte helt överensstämmande. Förslaget från Fall (2009) är kanske på så sätt mer korrekt, men är samtidigt mer komplicerat och därför eventuellt mer svårtillgängligt för både djurägare och kliniskt verksamma veterinärer. Med mer forskning på området kan man kanske finna en klassificering som är både korrekt och praktisk.
A keystone in the management of diabetes is nutritional therapy along with regular physical activity. Considering that most people with T2DM are overweight or obese, weight loss is recommended to improve glycemic control . In addition, regular physical activity has demonstrated significant health benefits . When lifestyle interventions fail in the appropriate control of glucose homeostasis, T2DM is initially treated by monotherapy with oral agents, and eventually, it may require the combination of multiple drugs. In this way, insulin sensitizers andinsulin secretagogues are safe therapies for T2DM treatment. Among the insulin sensitizers, metformin is successfully used as a first line pharmacotherapy for the treatment of T2DM patients. The major effect of this drug is the acute inhibition of hepatic gluconeogenesis through mechanisms involving the direct inhibition of the mitochondrial respiratory-chain complex I, leading to activation of AMP-activated protein kinase (AMPK) . The pleiotropic effects of metformin lead to lower fasting blood glucoseandinsulin levels with minimal risk of hypoglycemia .
Glycaemia, uric acid and plasma proteins were measured at baseline and 120 min after the OGTT (Dimension autoanalyzer; Dade Behring Inc., Deerfield, IL, USA). Measurements were also made in the baseline sample of total cholesterol, TAG and HDL-cholesterol by enzymatic methods in an autoanalyzer (Dimension; Dade Behring Inc.). Baseline insulin levels were measured by RIA administered by BioSource S.A. (Biosource Europe SA, Nivelles, Belgium) andinsulinresistance was calculated from the homeostasis model assessment (HOMA) with the formula: insulinresistance ¼ [fasting serum insulin (mU/ml) £ fasting blood glucose (mmol/l)]/22·5 24 and HOMA-IS ¼ (fasting insulin (mU/ml) £ 20)/(fasting glucose (mmol/l) 2 3.5).
dyslipidemia, fasting plasma glucose ≥ 100 mg/dL and/or a previous diagnosis of type 2 diabetes. HCV RNA was detected by COBAS Amplicor HCV PCR test version 2.0 (Roche Diagnostic Systems Inc., Nutley, NJ, USA) with a detection limit of 50 IU/mL and quantified using COBAS Amplicor HCV Monitor (Roche Diagnostic Systems Inc., Nutley, NJ, USA) with a detection limit of 200 IU/mL. IR was determined by HOMA-IR using the following formula: fasting glucose (mmol/L) multiplied by fasting insulin (mIU/L) divided by 22.5. For statis- tical analysis, continuous variables were expressed as mean ± standard deviation (SD). T-test or Mann-Whitney was used for comparison of varia- bles with or without normal distribution, respecti- vely. Qualitative data was expressed as proportions. Chi-square or Fisher’s Exact Test were used for comparison of variables depending on the number of results obtained in each observation. P-value was based on two-sided test, and alpha < 0.05 was considered statistically significant.
El músculo esquelético es uno de los principales tejidos blanco a la acción de la insulina. La regulación de este tejido envuelve una compleja interrelación con tance and adiposity. The goal of this work was to study in this animal model some metabolic pathways that might account for the lipid accumulation in the skeletal muscle and it relationship with dyslipidemia, altered insulin secretion from perifused islets and whole body insulinresistance. For this purpose male Wistar rats ini- tially weighting 180-190 g were fed during 30 weeks with a purified sucrose-rich diet (SRD) containing by weight (g/100g ): 63 sucrose, 17 casein free vitamins, 5 corn oil, 10 cellulose, 3.5 salt mixture (AIN-93MX), 1 vitamin mixture (AIN-93-VX), 0.2 choline and 0.3 DL-methionine. The control group received the same purified diet, but sucrose replaced by corn-starch [high starch diet (CD)]. The rats had free access to food and water and consumed their respective diets for up to 30 weeks. Both diets were isoenergetic and provided approxi- mately 15.28 kJ/g of food. Rats were fed “ad- libitum” during the complete experimental period. The following results were obtained: A) The biphasic patterns of glucose-stimulated insulin secretion from perifused islets showed an absence of the first peak with an increase of the second phase of hormone secretion. Moreover, compared to rats fed a control diet (CD) a significant reduction of the glucose infusion rate (GIR) was observed. Values were as follows: GIR (mg/kg.min.), mean ± SEM (n= 6), 4.3±0.80 in SRD vs 10±1.1 in CD (p<0.05). B) A significant increase (p<0.05) of both triglyceride and long-chain acyl -CoA contents in the gastrocnemius mus- cle was accompanied by an impaired capacity of glucose oxidation in the basal state and during the euglycemic –hyperinsulinemic clamp studies. This was mainly due to a decrease (p<0.05) of the active form of the pyru- vate dehydrogenase complex (PDHa) and an increase of the PDH-Kinase activities (p<0.05). A significant reduc- tion of the flux through the PDH complex may limit glucose oxidation via glucose-fatty acid cycle of Randle. Besides, an impaired non-oxidative pathway of glucose was recorded at the end of the clamp. The glycogen synthase activity was significantly lower (p<0.05) as compared with age matched control rats fed a CD. Furthermore, a decreased insulin-stimulated glycogen store was observed. C) A high level of both long-chain acyl -CoA and diacylglycerol within the skeletal muscle could stimulate an increase and translocation of nPKC θ
Bile acids (BAs), the end products of cholesterol catabolism, are essential for the absorption of lipids and fat-soluble vitamins; but they have also emerged as novel signaling molecules that act as metabolic regulators. It has been well described that the enterohe- patic circulation, a nuclear (FXR) and a cytoplasmic (TGR5/M-BAR) receptor aid in controlling hepatic bile acid synthesis. Modulat- ing bile acid synthesis greatly impacts inmetabolism, because these receptors also are implicated inglucose, lipid, and energy expenditure. Recent studies had revealed the way these receptors participate in regulating gluconeogenesis, peripheral insulin sensi- tivity, glycogen synthesis, glucagon like peptide 1 (GLP-1) andinsulin secretion. Nowadays, it is demonstrated that enhancing bile acid signaling in the intestine contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery on glucose homeos- tasis. This paper discusses the role of bile acid as regulators of glucosemetabolismand their potential as therapeutic targets for dia- betes.
Introduction. Obesity is considered a public health problem. Its presence at an early age implies an obligation to identify the onset of complications such as insulinresistanceand diabetes mellitus (DM). Methods. Observational, descriptive and transversal study. Participated 1206 teenage women. Obesity was defined with BMI values ≥95p according WHO. Serum levels of insulin, glucoseand lipid profile were determined. The Homeostasis Model of Assesment Index (HOMA-I) was used, using the Matthews equation with the value ≥ 3,16 to define insulinresistance (RI). For dyslipidemias: hypercholesterolemia ≥ 200 mg/dL, low HDL-C ≤ 40 mg/dL, high C-LDL ≥ 130 mg / dL and hypetriglyceridemia ≥ 130 mg/dL. The obese teenagers with RI underwent an oral glucose tolerance test (PTG): glycemia of 140 to 199 mg / dL intolerant to glucoseand ≥ 200 mg/dL as diabetic. Results 25,1% (303) of the population was obese; 246 obese adolescents participated in the biochemical evaluation, 28,1% (69) of them presented RI. In the obese teenagers with and without IR, the average of the biochemical variables in the former were higher, these differences being statistically significant, except for HDL-C. Differences between the prevalence of dyslipidemias were significant except for HDL-C. The IR presented an OR of 10,9 (CI 5,4-26,6), 12,1 (CI 4,9-30,1), and 7,6 (CI 3-19,5) with hypertriglyceridemia, hypercholesterolemia and high LDL-C. The PTG showed 3,3% intolerant and none diabetic. Conclusions: 28,1% (69) of obese adolescents presented RI; no study participant presented DM.
The energy sensing enzyme AMPK has been the focus of many investigation and is considered an attractive anti-diabetic target. A major aim of this thesis was to delineate the mechanisms governing the AMPK activity in skeletal muscle. One challenge is to develop a drug that is specific to AMPK. The question remains whether a drug that specifically activates AMPK would yield therapeutic effects without having deleterious side effects. AICAR, the most widely used AMPK activator has positive effects on metabolism. However, this drug is a long way from clinical treatment of insulinresistanceand type 2 diabetes, since it is not specific to AMPK and it activates several other kinases. One way to activate the AMPK system as highlighted in this thesis would be to alter the expression of AMP-metabolizing enzymes, such as 5- nucleotidases and ATIC. Silencing of 5’-nucleotidases, NT5C1A and NT5C2 in rodent muscle and human skeletal muscle cell culture respectively increased AMPK and ACC phosphorylation and enhanced glucoseand lipid metabolism, indicating their role in restoring skeletal muscle energy homeostasis. These results provide proof-of-principle that skeletal muscle specific inhibitors of 5’-nucleotidases enzymes may be beneficial to improve metabolismin type 2 diabetes. Since this approach was skeletal muscle specific, deleterious cardiac effects could be avoided. This thesis investigated the transient effects of inhibition of 5´-nucleotidases. Future studies to assess the consequence of long-term inhibition of 5’-nucleotidases enzymes is warranted.
The evidences reviewed here led us to propose the buff- ering effi ciency hypothesis (fi gure 1). LPS is an impor- tant factor that might produce insulinresistanceand obesity in humans. Chronic low-grade infl ammation and associated insulinresistance might be viewed in the con- text of an unbalanced innate immune system. A de- creased production of anti-LPS proteins and peptides were associated with insulinresistance, obesity, vascular dysfunction, hepatic dysfunction and dyslipidemia. A partial lost in the buffering effi ciency of LPS could in- crease its negative effects on metabolism. Furthermore, insulinresistance might result in a decreased concentra- tion of those proteins that buffer LPS. It is well known that adiponectin production by the adipose tissue is de- creased under insulinresistanceand infl ammatory con- ditions. Neutrophils also lose antimicrobial effi ciency ininsulin resistant conditions, decreasing the production of lactoferrin, BPI and other antimicrobial proteins. Neu- trophil activity may be restored by controlling hypergly- cemia using insulin. 80,81
Our study design also allowed us to investigate the relationship between FASN mRNA expression and serum concentrations of adipocytokines (leptin and adi- ponectin). We found a correlation between FASN and serum concentrations of adiponectin. These adipocyto- kines are also BMI dependent in obesity while leptin increases, adiponectin decreases. According to sex we can also see that both are present in higher concentra- tions in women than in men. Leptin could directly sup- press FASN mRNA expression in adipose tissue, since experimentally increased plasma leptin concentrations in rats resulted in a decrease of FASN mRNA levels in fat . There are data supporting a suppressive action of leptin on FAS transcription . Adiponectin is an exclusively adipocyte-derived hormone  with a key role inglucoseand lipid metabolismin skeletal muscle and the liver, acting as an insulin sensitizer . It is the only adipocytokine known to be down-regulated in obesity  andinsulinresistance by decreasing TG content in muscle and liver . Hypoadiponectinemia has been more closely related to the degree of insulinresistanceand hyperinsulinemia than the degree of adip- osity .
We used 3-months old male mice that were treated with Epoxy at 200 mg/kg body weight. Glucose intolerance was induced by multiple intraperitoneal low-doses of streptozotocin (STZ) on 5 consecutive days. Glucose homeostasis was evaluated measuring plasma insulin levels andglucose tolerance. Histomorphometry was used to quantify the number of pancreatic b-cells per islet. b-cell proliferation was assessed by BrdU incorporation, and apoptosis by TUNEL staining. Epoxy treatment signi ﬁ cantly improved glucose tolerance and plasma insulin levels. These metabolic changes were associated with increased b-cell numbers, as a result of a two-fold increase in b-cell proliferation and a 50% decrease in b-cell death.
for lipoatrophic patients. However, rosiglitazone should be used with caution in hyperlipidemic patients. If used, this must be accompanied by careful monitoring of the lipid profile. Treatment with metformin is not recommended in patients with renal– or liver disease or elevated lactic acid levels. Regarding TZDs, it is important to note that rosiglitazone is a substrate for CYP2C8 and is unlikely to affect CYP3A4 metabolism on concomitantly administrated drugs, such as PIs. Future studies are necessary to investigate the effects of combination therapy with rosiglitazone and metformin in HIV-infected patients. In addition, dual PPAR- α/γ agonists may be useful to treat both dyslipidemia and lipodystrophy in HIV-infected patients in the future.
In total, 130 patients were included. The clinical and biochemical characteristics are shown in tables 1 and 2. The mean age was 55.6 ± 11.4 years. Fami- ly history of DM (at least one first-line family mem- ber affected) was identified in 16 patients (12.3%), 22 (36%) had hypertriglyceridemia (serum triglyce- rides > 150 mg/dL), and 18 (13.8%) had arterial hy- pertension. Seventeen of the 43 (32%) patients with diabetes were treated with insulinand 16 (30%) with oral hypoglycemic drugs. The most patients (69%) were overweight or obese, and the etiology of cirrho- sis was predominantly alcoholic and cryptogenic (50.7 and 28.4%, respectively). The diagnosis of cirr- hosis was made by liver biopsy in 42 (32.3%) pa- tients. Half of the patients belonged to Child-Pugh Group A (50.7%) and had a mean MELD score of 10.3 ± 4.8. The most significant abnormalities found in laboratory tests were: hypercreatininemia (serum creatinine > 1.2 mg/dL) in 15 (11.5%) pa- tients and hypoalbuminemia (serum albumin < 3.5 mg/dL) in 77 (59.2%) patients.
Liver homogenates were collected and diluted 1:100 in duplicate in hydrolysis buffer up to a final volume of 50 µL. To one of the duplicates 2 µL of hydrolysis enzyme mix were added; while, to the other duplicates 2 µL of ultrapure water were added. These last samples were used as controls of hepatic glucose content in each liver. After that, the microplate was incubated for 30 min at room temperature. Then, 50 µL of master reaction mix, which contains the development buffer (46 µL), the development enzyme mix (2 µL) and the fluorescent peroxidase substrate (2 µL), was added to each well and incubated for 30 min at room temperature. During the reaction incubation, the plate was protected from light. Finally, the microplate was read spectrophotometrically at a wavelength of 562 nm using a microplate reader (Heales, China). The intensity of this colored product is directly proportional to the concentration of glycogen present in the original specimen. A standard curve of known concentration can be established accordingly. The unknown concentration in samples can be determined by reference to this standard curve.
Seventy-six Caucasian men were recruited and studied in an ongoing study dealing with nonclassical cardiovascular risk fac- tors in northern Spain. Subjects were randomly localized from a census and they were invited to participate. The participation rate was 71%. A 75-g oral glucose tolerance test according to the American Diabetes Association Criteria was performed in all subjects. Subject characteristics and inclusion criteria were de- tailed in the Supplemental Data, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals. org. All subjects gave written informed consent after the purpose of the study was explained to them. The Ethical Committee of the Hospital Universitari Dr Josep Trueta approved the protocol.
scription of several major genes in the lipids metabolism, for instance CPT1A (mitochondrial carnitine palmitoyl acyl-CoA transferase 1), which is a rate limiting enzyme in the mitochondrial β -oxidation mediating the entry of fatty acids in the mitochondria; ACOX (acyl-CoA oxi- dase), the main enzyme in mitochondrial β -oxidation; and Mdr2, a transport protein in canalicula membranes which controls biliary phospholipids secretion. Several experimental models showed a diminished PPAR- α ex- pression and transcriptional activity, with a decreased CPT1A and ACOX expression with decreased fatty acids oxidation, as well as a decreased Mdr2 expression with a potential decrease in phospholipids associated fatty ac- ids biliary excretion. 88-91
Objetivo: Evaluar la existencia de correlación entre los niveles de osteocalcina sérica y marcadores de in- sulinorresistencia (IR) e insulinosensibilidad en una población de adultos mayores con síndrome metabólico. Material y métodos: En nuestro estudio prospectivo se incluyeron 88 pacientes (68 % mujeres, 32 % hom- bres, media de edad 73 ± 6 y 74 ± 6 años respectivamente) que concurrieron a los consultorios externos del servicio de Endocrinología y Metabolismo del hospital Dr. César Milstein. Todos cumplían con los criterios diagnósticos de síndrome metabólico del año 2009 de la Federación Internacional de Diabetes (IDF). Se midieron: osteocalcina sérica, hemoglobina glicosilada (HbA1c), HDL y triglicéridos (TG). Se calcularon QUICKI (Quantitative Insulin Sensivity Check Index) y el índice TG/HDL.
The link between ER stress andinsulinresistancein skeletal muscle is less understood. Presently, only a few studies have reported the presence of ER stress in skeletal muscle of obese and type 2 diabetic animal models. In mice, ER stress markers are elevated after 6 and 20 weeks of HFD (Deldicque, Cani et al. 2010). Palmitic acid has been shown to induce ER stress in C2C12 and L6 muscle cells (Peng, Li et al. 2011; Hage Hassan, Hainault et al. 2012; Rieusset, Chauvin et al. 2012). However, the mechanism of ER stress and its effect on insulin sensitivity has been divergent in these studies. Peng et al. have demonstrated that treatment with 4-phenyl butyric acid (4-PBA), a chemical chaperone, alleviates palmitate-induced ER stress in C2C12 and L6 cell lines and improves insulin signaling andglucose uptake. Interestingly, the addition of oleate to the medium has a similar effect as 4-PBA and protects the cells from palmitate-induced ER stress andinsulinresistance. On the other hand, in two other studies the prevention of palmitate- induced ER stress with the chemical chaperones 4-PBA or tauroursodeoxycholic acid (TUDCA), a taurine-conjucated derivative of bile acids, does not prevent palmitate- induced insulinresistance. In addition, although overexpression of the chaperon protein BiP reduces ER stress in C2C12 cells, this does not improve reduced insulin action induced by palmitate (Rieusset, Chauvin et al. 2012). When muscle cells are treated with tunicamycin (an inhibitor of protein glycosylation that induces ER stress) and with chemical chaperones, the gene expression of the UPR pathway is decreased. The negative effect of tunicamycin on insulin action is also prevented (Rieusset, Chauvin et al. 2012). Similar effect of chaperones is also seen on glucosamine (GlcN)-induced insulinresistance (Raciti, Iadicicco et al. 2010).
29. Klein DJ, Aronson Friedman L, Harlan WR, Barton BA, Schreiber GB, Cohen RM, et al. Obesity and the development of insulinresistanceand impaired fasting glucosein black and white adolescent girls. Diabetes Care. 2004;27:378-83. 30. Goran M, Bergman R, Cruz M, Watanabe R. Insulinresistanceand associated compensatory responses in African- American and Hispanic children. Diabetes Care. 2002;25:2184-90.