Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is growing evidence that the type of carbohydrate consumed is important in relation to metabolic disease risk, and there is currently particular interest in the role of low-glycaemic-index (GI) foods. Observational studies have associated low-GI diets with decreased risk of type 2 diabetes and CHD, and improvements in various metabolic risk factors have been seen in some intervention studies. However, findings have been mixed and inconsistent. There are a number of plausible mechanisms for the effects of these foods on disease risk, which arise from the differing metabolic responses to low- and high-GI foods, with low-GI foods resulting in reductions in hyperglycaemia, hyperinsulinaemia and late postprandial circulating NEFA levels. Low-GI foods may also increase satiety and delay the return of hunger compared with high-GI foods, which could translate into reduced energy intake at later time points. However, the impact of a low-GI diet on body weight is controversial, with many studies confounded by dietary manipulations that differ in aspects other than GI. There is currently much interest in GI from scientists, health professionals and the public, but more research is needed before clear conclusions can be drawn about relationships with metabolic disease risk.
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PMID:Glycaemic index and metabolic disease risk. 1644 52

The PPARgamma Pro12Ala polymorphism has been associated in several studies with a decreased risk of obesity, type 2 diabetes and insulin resistance. Weak hints are available about the influence of PPARgamma Pro12Ala on postprandial metabolism. In 708 men, aged 45 to 65 years the PPARgamma2 Pro12Ala genotypes were determined and postprandial TAG, insulin, glucose and NEFA after a standardized mixed fat meal and insulin and glucose after a glucose load (oral glucose tolerance test; OGTT) were assessed. Using the total sample, we did not find a significant impact of the genotype on the postprandial metabolism. In the subgroup with BMI <30 kg/m2, fasting and postprandial TAG and insulin levels as well as homeostasis model assessment of insulin resistance (HOMA) were significantly lower in the Ala12Ala group than in the Pro12Pro group after the mixed meal. In contrast, the groups did not differ in insulin levels and HOMA after the OGTT. To investigate if differences between a fat-containing meal and OGTT are caused by adiponectin, we examined a BMI- and age-matched subgroup. No differences were found between the genotypic groups. The effects of the PPARgamma2 polymorphism on insulin sensitivity are mediated by affluent dietary fat. We did not find evidence that adiponectin as a fatty-acid-dependent adipocyte factor is a causative factor for this phenomenon.
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PMID:The minor allele of the PPARgamma2 pro12Ala polymorphism is associated with lower postprandial TAG and insulin levels in non-obese healthy men. 1740 25

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.
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PMID:Session 7: Early nutrition and later health early developmental pathways of obesity and diabetes risk. 1763 98

Human mitochondria can be studied either in biopsies or by measuring flux through ATP synthase and phosphocreatine recovery using magnetic resonance spectroscopy. Myocellular ATP production (flux through ATP synthase [fATP]) increases by up to 90% during 8 h of insulin stimulation. Fasting mitochondrial function is 14-40% lower than in controls in the presence of insulin resistance, as seen in those with type 2 diabetes, their insulin-resistant relatives or the obese. Insulin-stimulated fATP is abolished in insulin-resistant relatives and patients with type 2 diabetes, and patients frequently show decreased mitochondrial size/density. Age, fat mass, physical activity, plasma NEFA and glucose all correlate negatively with mitochondrial function, but it is for methodological reasons difficult to determine whether reduced mitochondrial content or function account for reduced ATP production in insulin resistance. Experimental plasma NEFA elevation appears to inhibit mitochondrial function by interfering with the metabolic actions of insulin, which might explain impaired mitochondrial function in obesity. Alternatively, primary mitochondrial abnormalities, as seen in those with inherited risk of type 2 diabetes, could decrease lipid oxidation, thereby raising circulating and intracellular NEFA levels. In type 2 diabetes, chronic hyperglycaemia and dyslipidaemia could first diminish the function, and subsequently reduce the size or density of mitochondria via oxidative stress and apoptosis. Many questions remain unsolved, including (1) which mechanisms regulate mitochondrial adaptation to nutrient overload; (2) what factors control the expression of genes encoding mitochondrial proteins and other signals involved in mitochondrial biogenesis; (3) which geno/phenotypes are associated with both insulin resistance and mitochondrial abnormalities; and (4) which are the most promising targets for improving mitochondrial fitness in insulin resistance?
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PMID:Mitochondrial fitness and insulin sensitivity in humans. 1880 78

Twenty Simmental x Angus, half-sibling, postpubertal heifers (initial BW of 443 +/- 9 kg) were allotted randomly into 2 treatment groups to evaluate if initial BCS affects response of the hypothalamic-pituitary-ovarian axis to metabolic signals elicited by energy restriction and repletion. During a preliminary feeding period, diets were formulated so that each heifer in the designated treatment would reach a BCS of 5 (moderate condition; MOD) or a BCS of 7 (heavy condition; FAT). Once each heifer had reached desired BCS, diets were formulated to supply 30% of NE(m) requirements until each heifer became anestrous (serum concentrations of progesterone < 1 ng/mL; restriction period). Blood collections took place on d 1 of each period, on d 43 of energy restriction and d 44 of energy repletion, and when heifers were confirmed to recommence estrous cycles. When heifers were cycling, their estrous cycles were synchronized to ensure hormone sampling occurred during late diestrus or early proestrus. Energy restriction resulted in decreased concentrations of LH (FAT, P = 0.02; MOD, P < 0.001), IGF-1 (FAT, P < 0.001; MOD, P = 0.003), and insulin (P < 0.001); in contrast, concentrations of GH (P < 0.001) and plasma urea nitrogen (P < 0.001) increased. During repletion, LH concentration increased (P = 0.03) in MOD condition heifers but was still less (P = 0.002) than d 1 of restriction, whereas LH concentration tended to increase in FAT heifers (P = 0.06) until it was similar (P = 0.40) to d 1 of restriction. Repletion also increased concentrations of IGF-1 (P < 0.001), insulin (P < 0.001), and glucose (P < 0.001), whereas concentrations of GH (P < 0.001), NEFA (P < 0.001), and plasma urea nitrogen (P < 0.001) decreased. For both treatments, concentrations of GH after repletion were similar (FAT, P = 0.88; MOD, P = 0.10) to those on d 1 of restriction. After repletion, FAT condition heifers had decreased concentrations of IGF-1 (P < 0.001), insulin (P < 0.05), and glucose (P < 0.001), but greater concentrations of acetate (P < 0.01) and butyrate (P < 0.05), than MOD heifers. Anestrus or resumption of estrous cycles seems to be activated gradually in response to dietary manipulation, unrelated to certain metabolite changes.
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PMID:Initial body condition score affects hormone and metabolite response to nutritional restriction and repletion in yearling postpubertal beef heifers. 1935 2

Metabolic substrate utilization of the human failing heart is an area of controversy. The purpose of this study is to directly quantify myocardial substrate utilization in moderately severe heart failure, type 2 diabetes and healthy controls using simultaneous coronary sinus and arterial blood sampling. Patients with heart failure (n = 9, mean NYHA 2.7+/-0.5), with type 2 diabetes (n = 5) and with normal heart function (n = 10) were studied after an overnight fast in connection with electrophysiological investigations/treatments.A systemic infusion of [(2)H(2)]palmitate allowed for the calculation of absolute palmitate extraction across the heart. Blood samples were analysed for non-esterified fatty acids, triacylglycerol, glycerol, glucose, pyruvate, lactate, 3-hydroxybutyrate, and blood gases after simultaneous sampling of arterial and coronary sinus blood. Arterio-coronary sinus metabolite concentration differences and fractional extractions for all substrates were similar between the groups. The absolute NEFA uptakes assessed by [(2)H(2)]palmitate extraction were also similar between the groups. Using direct measurements of metabolic substrate uptake by arterio-venous difference technique, the compensated human failing heart does not appear to have reduced myocardial fatty acid uptake.
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PMID:Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. 1984 74

Inflammation plays an important role in diabetes mellitus and its complications. In this context, the negative cross-talk between adipose tissue and skeletal muscle leads to disturbances in muscle cell insulin signalling and induces insulin resistance. Because several studies have shown that energy restriction brings some benefits to diabetes, the aim of the present study was to evaluate the effects of dietary restriction on systemic and skeletal muscle inflammatory biomarkers, such C-reactive protein, adipokines and cytokines, and in insulin resistance in Goto-Kakizaki rats. This is an animal model of spontaneous non-obese type 2 diabetes with strongly insulin resistance and without dyslipidaemia. Animals were maintained during 2 months of dietary restriction (50 %) and were killed at 6 months of age. Some biochemical determinations were done using ELISA and Western blot. Data from the present study demonstrate that in Goto-Kakizaki rats the dietary restriction improved insulin resistance, NEFA levels and adipokine profile and ameliorated inflammatory cytokines in skeletal muscle. These results indicate that dietary restriction in type 2 diabetes enhances adipose tissue metabolism leading to an improved skeletal muscle insulin sensitivity.
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PMID:Beneficial effects of dietary restriction in type 2 diabetic rats: the role of adipokines on inflammation and insulin resistance. 2017 70

The purpose of the present study was to investigate the sex hormonal and metabolic profiles in vegetarians and compare these with the profiles in omnivores. The design of the present study was cross-sectional. The study sample of pre- and post-menopausal women included forty-one omnivores and twenty-one vegetarians. Thereafter we determined: (1) plasma sex hormones, (2) fasting insulin, NEFA as well as apo-A and apo-B, (3) BMI, (4) a dietary profile (3 d dietary records), (5) physical activity and (6) total faecal excretion per 72 h and total urinary excretion per 72 h. Vegetarians showed higher levels of sex hormone-binding globulin (SHBG), apo-A, total faecal excretion per 72 h and total fibre intake as well as lower levels of apo-B, free oestradiol, free testosterone, dehydroepiandrosterone sulfate (DHEA-s) and BMI. Interestingly, after controlling for BMI, significant differences between groups still persisted except for apo-B. Moreover, stepwise regression analysis showed that total fibre intake explained 15.2 % of the variation in SHBG in our cohort, which accounted for the greatest source of unique variance. Results of the present study indicate that pre- and post-menopausal vegetarians present higher concentrations of SHBG, which could be explained, in part, by higher levels of fibre intake. This may explain, at least in part, the lower risk of developing type 2 diabetes.
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PMID:Comparison of sex hormonal and metabolic profiles between omnivores and vegetarians in pre- and post-menopausal women. 2021 Oct 44

EPA or fish oil supplementation has been suggested as treatments for the prevention of type 2 diabetes mellitus (T2DM) due to their lipid-lowering and potential insulin-sensitising effects. We investigated the effects of supplementation with EPA (1 g/kg body weight per d) or fish oil (3 g/kg body weight per d) on the age of onset of T2DM and circulating glucose, insulin, lipids, leptin and adiponectin in UC Davis (UCD)-T2DM rats. Animals were divided into three groups starting at 1 month of age: control, EPA and fish oil. All the animals were followed until diabetes onset or for up to 12 months of age. Monthly fasting blood samples were collected for the measurement of glucose, lipids, hormones and C-reactive protein (CRP). Neither EPA nor fish oil delayed the onset of T2DM or altered fasting plasma glucose, insulin, CRP, adiponectin or leptin concentrations. The groups did not differ in energy intake or body weight. Fish oil treatment lowered fasting plasma TAG concentrations by 39 (sd 7) % (P < 0.001) and EPA lowered fasting plasma NEFA concentrations by 23 (sd 5) % (P < 0.05) at 4 months of age compared with the control group. EPA and fish oil lowered fasting plasma cholesterol concentrations at 4 months of age by 19 (sd 4) and 22 (sd 4) % compared with the control group, respectively (both P < 0.01). In conclusion, EPA and fish oil supplementation lowers circulating lipid concentrations, but does not delay the onset of T2DM in UCD-T2DM rats.
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PMID:Supplementation with EPA or fish oil for 11 months lowers circulating lipids, but does not delay the onset of diabetes in UC Davis-type 2 diabetes mellitus rats. 2073 78

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.
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PMID:Targeting energy expenditure via fuel switching and beyond. 2095 61


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