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1.  Mendelian Randomization Studies do not Support a Role for Raised Circulating Triglyceride Levels influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance 
Diabetes  2011;60(3):1008-1018.
Objective
The causal nature of associations between circulating triglycerides, insulin resistance and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes, raised normal fasting glucose levels, and hepatic insulin resistance.
Research design and methods
We tested 10 common genetic variants robustly associated with circulating triglyceride levels against type 2 diabetes status in 5637 cases, 6860 controls, and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8271 non-diabetic individuals from four studies.
Results
Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (0.59 SD [95% CI: 0.52, 0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio (OR) 0.99 [95% CI: 0.97, 1.01]; P = 0.26). In non-diabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (0.00 SD per weighted allele [95% CI: −0.01, 0.02]; P = 0.72) or increased fasting glucose levels (0.00 SD per weighted allele [95% CI: −0.01, 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose or fasting insulin, and, for diabetes, showed a trend towards a protective association (OR per 1 SD increase in log10-triglycerides: 0.61 [95% CI: 0.45, 0.83]; P = 0.002).
Conclusion
Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes, or raise fasting glucose or fasting insulin levels in non-diabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
doi:10.2337/db10-1317
PMCID: PMC3046819  PMID: 21282362
2.  A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo 
Background
Cycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points.
Methods/Design
3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.
Discussion
This study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens.
Trial registration
clinical trials.gov NCT00377676
doi:10.1186/1472-6823-7-3
PMCID: PMC1924849  PMID: 17592632
3.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
RESULTS
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
CONCLUSIONS
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
doi:10.2337/db11-0415
PMCID: PMC3178302  PMID: 21873549
4.  Genome-Wide Linkage Scan for Genes Influencing Plasma Triglyceride Levels in the Veterans Administration Genetic Epidemiology Study 
Diabetes  2009;58(1):279-284.
OBJECTIVE—Elevated plasma triglyceride concentration is a component of the insulin resistance syndrome and is commonly associated with type 2 diabetes, obesity, and coronary heart disease. The goal of our study was to perform a genome-wide linkage scan to identify genetic regions that influence variation in plasma triglyceride levels in families that are enriched with individuals with type 2 diabetes.
RESEARCH DESIGN AND METHODS—We used phenotypic and genotypic data from 1,026 individuals distributed across 294 Mexican-American families, who were ascertained for type 2 diabetes, from the Veterans Administration Genetic Epidemiology Study (VAGES). Plasma triglyceride values were transformed, and a variance-components technique was used to conduct multipoint linkage analysis.
RESULTS—After adjusting for the significant effects of sex and BMI, heritability for plasma triglycerides was estimated as 46 ± 7% (P < 0.0001). Multipoint linkage analysis yielded the strongest evidence for linkage of plasma triglycerides near marker D12S391 on chromosome 12p (logarithm of odds [LOD] = 2.4). Our linkage signal on chromosome 12p provides independent replication of a similar finding in another Mexican-American sample from the San Antonio Family Diabetes Study (SAFDS). Combined multipoint linkage analysis of the VAGES and SAFDS data yielded significant evidence for linkage of plasma triglycerides to a genetic location between markers GATA49D12 and D12S391 on 12p (LOD = 3.8, empirical P value = 2.0 × 10−5). This region on 12p harbors the gene-encoding adiponectin receptor 2 (AdipoR2), where we previously have shown that multiple single nucleotide polymorphisms are associated with plasma triglyceride concentrations in the SAFDS. In the present study, we provided suggestive evidence in favor of association for rs929434 with triglyceride concentrations in the VAGES.
CONCLUSIONS—Collectively, these results provide strong evidence for a major locus on chromosome 12p that influences plasma triglyceride levels in Mexican Americans.
doi:10.2337/db08-0491
PMCID: PMC2606886  PMID: 18931038
5.  Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content 
Diabetes  2008;57(9):2288-2295.
OBJECTIVE—Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes.
RESEARCH DESIGN AND METHODS—Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by 1H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging.
RESULTS—Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 ± 1.0 vs. 12.2 ± 0.7 μmol · kg−1 · min−1, P = 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 ± 0.25 vs. 1.26 ± 0.30 μmol · kg−1 · min−1, P < 0.001). Hepatic triglyceride content decreased by ∼50% (P = 0.03), and muscle (anterior tibialis) triglyceride content decreased by ∼55% (P = 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r = 0.64, P = 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r = −0.63, P = 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP.
CONCLUSIONS—Reduction in hepatic triglyceride by pioglitazone is very closely related to improvement in fasting and postprandial EGP in type 2 diabetes.
doi:10.2337/db07-1828
PMCID: PMC2518479  PMID: 18535187
6.  Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream 
PLoS Medicine  2008;5(8):e155.
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Using a Mendelian randomization approach, Eric Brunner and colleagues show that the associations between serum C-reactive protein and insulin resistance, glycemia, and diabetes are likely to be noncausal.
Editors' Summary
Background.
Diabetes—a common, long-term (chronic) disease that causes heart, kidney, nerve, and eye problems and shortens life expectancy—is characterized by high levels of sugar (glucose) in the blood. In people without diabetes, blood sugar levels are controlled by the hormone insulin. Insulin is released by the pancreas after eating and “instructs” insulin-responsive muscle and fat cells to take up the glucose from the bloodstream that is produced by the digestion of food. In the early stages of type 2 diabetes (the commonest type of diabetes), the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance), and blood sugar levels increase. The pancreas responds by making more insulin—people with insulin resistance have high blood levels of both insulin and glucose. Eventually, however, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and frank diabetes develops.
Why Was This Study Done?
Globally, about 200 million people have diabetes, but experts believe this number will double by 2030. Ways to prevent or delay the onset of diabetes are, therefore, urgently needed. One major risk factor for insulin resistance and diabetes is being overweight. According to one theory, increased body fat causes mild, chronic tissue inflammation, which leads to insulin resistance. Consistent with this idea, people with higher than normal amounts of the inflammatory protein C-reactive protein (CRP) in their blood have a high risk of developing diabetes. If inflammation does cause diabetes, then drugs that inhibit CRP might prevent diabetes. However, simply measuring CRP and determining whether the people with high levels develop diabetes cannot prove that CRP causes diabetes. Those people with high blood levels of CRP might have other unknown factors in common (confounding factors) that are the real causes of diabetes. In this study, the researchers use “Mendelian randomization” to examine whether increased blood CRP causes diabetes. Some variants of CRP (the gene that encodes CRP) increase the amount of CRP in the blood. Because these variants are inherited randomly, there is no likelihood of confounding factors, and an association between these variants and the development of insulin resistance and diabetes indicates, therefore, that increased CRP levels cause diabetes.
What Did the Researchers Do and Find?
The researchers measured blood CRP levels in more than 5,000 people enrolled in the Whitehall II study, which is investigating factors that affect disease development. They also used the “homeostasis model assessment-insulin resistance” (HOMA-IR) method to estimate insulin sensitivity from blood glucose and insulin measurements, and measured levels of hemoglobin A1c (HbA1c, hemoglobin with sugar attached—a measure of long-term blood sugar control) in these people. Finally, they looked at three “single polynucleotide polymorphisms” (SNPs, single nucleotide changes in a gene's DNA sequence; combinations of SNPs that are inherited as a block are called haplotypes) in CRP in each study participant. Common haplotypes of CRP were related to blood serum CRP levels and, as previously reported, increased blood CRP levels were associated with diabetes and with HOMA-IR and HbA1c values indicative of insulin resistance and poor blood sugar control, respectively. By contrast, CRP haplotypes were not related to HOMA-IR or HbA1c values. Similarly, pooled analysis of CRP haplotypes and diabetes in Whitehall II and another large study on health determinants (the Northwick Park Heart Study II) showed no association between CRP variants and diabetes risk. Finally, data from the Wellcome Trust Case Control Consortium also showed no association between CRP haplotypes and diabetes risk.
What Do These Findings Mean?
Together, these findings suggest that increased blood CRP levels are not responsible for the development of insulin resistance or diabetes, at least in European populations. It may be that there is a causal relationship between CRP levels and diabetes risk in other ethnic populations—further Mendelian randomization studies are needed to discover whether this is the case. For now, though, these findings suggest that drugs targeted against CRP are unlikely to prevent or delay the onset of diabetes. However, they do not discount the possibility that proteins involved earlier in the inflammatory process might cause diabetes and might thus represent good drug targets for diabetes prevention.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050155.
This study is further discussed in a PLoS Medicine Perspective by Bernard Keavney
The MedlinePlus encyclopedia provides information about diabetes and about C-reactive protein (in English and Spanish)
US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on all aspects of diabetes, including information on insulin resistance (in English and Spanish)
The International Diabetes Federation provides information about diabetes, including information on the global diabetes epidemic
The US Centers for Disease Control and Prevention provides information for the public and professionals on all aspects of diabetes (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050155
PMCID: PMC2504484  PMID: 18700811
7.  Hepatic PTP1B Deficiency: The Promise of a Treatment for Metabolic Syndrome? 
Metabolic syndrome and type 2 diabetes are complex disorders that are associated with obesity, aging, and genetic predisposition. The increasing prevalence of metabolic abnormalities worldwide presents a serious public health problem, with rates of obesity and diabetes reaching unprecedented levels. A common feature of these disorders is the development of insulin resistance, resulting in decreased insulin-stimulated glucose uptake, failure to suppress hepatic glucose production, and accumulation of hepatic lipid. Recent studies in mice have shown that deficiency of the non-receptor protein tyrosine phosphatase, PTP1B, in liver leads to a host of improvements in metabolic parameters, including improved hepatic insulin sensitivity, reduced liver triglycerides, lower serum and hepatic cholesterol levels, and protection against high-fat diet-induced endoplasmic reticulum (ER) stress. Based on these promising studies, PTP1B inhibitors may prove to be a valuable therapeutic tool in the fight against metabolic syndrome and its associated comorbidities. In this review, the role of PTP1B in hepatic insulin sensitivity, hepatic lipid accumulation, and ER stress are discussed.
PMCID: PMC3083115  PMID: 21533018
Metabolic syndrome; diabetes; PTP1B; liver; insulin; phosphatase
8.  Tuberous Sclerosis Complex-1 Deficiency Attenuates Diet-Induced Hepatic Lipid Accumulation 
PLoS ONE  2011;6(3):e18075.
Non-alcoholic fatty liver disease (NAFLD) is causally linked to type 2 diabetes, insulin resistance and dyslipidemia. In a normal liver, insulin suppresses gluconeogenesis and promotes lipogenesis. In type 2 diabetes, the liver exhibits selective insulin resistance by failing to inhibit hepatic glucose production while maintaining triglyceride synthesis. Evidence suggests that the insulin pathway bifurcates downstream of Akt to regulate these two processes. Specifically, mTORC1 has been implicated in lipogenesis, but its role on hepatic steatosis has not been examined. Here, we generated mice with hepatocyte-specific deletion of Tsc1 to study the effects of constitutive mTORC1 activation in the liver. These mice developed normally but displayed mild hepatomegaly and insulin resistance without obesity. Unexpectedly, the Tsc1-null livers showed minimal signs of steatosis even under high-fat diet condition. This ‘resistant’ phenotype was reversed by rapamycin and could be overcome by the expression of Myr-Akt. Moreover, rapamycin failed to reduce hepatic triglyceride levels in models of steatosis secondary to Pten ablation in hepatocytes or high-fat diet in wild-type mice. These observations suggest that mTORC1 is neither necessary nor sufficient for steatosis. Instead, Akt and mTORC1 have opposing effects on hepatic lipid accumulation such that mTORC1 protects against diet-induced steatosis. Specifically, mTORC1 activity induces a metabolic shift towards fat utilization and glucose production in the liver. These findings provide novel insights into the role of mTORC1 in hepatic lipid metabolism.
doi:10.1371/journal.pone.0018075
PMCID: PMC3066210  PMID: 21479224
9.  Liver Fat Content in Type 2 Diabetes: Relationship With Hepatic Perfusion and Substrate Metabolism 
Diabetes  2010;59(11):2747-2754.
OBJECTIVE
Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content.
RESEARCH DESIGN AND METHODS
Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%.
RESULTS
Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = −0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = −0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = −0.329, P = 0.004).
CONCLUSIONS
In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat on hepatic physiology.
doi:10.2337/db09-1201
PMCID: PMC2963532  PMID: 20693345
10.  Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Women and Men 
The New England journal of medicine  2009;361(12):1152-1163.
BACKGROUND
Circulating sex hormone–binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.
METHODS
We performed a nested case–control study of postmenopausal women in the Women’s Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone–binding globulin were measured; two polymorphisms of the gene encoding sex hormone–binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians’ Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls).
RESULTS
Among women, higher plasma levels of sex hormone–binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone–binding globulin levels (P = 0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P = 0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone–binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone–binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone–binding globulin may have a causal role in the risk of type 2 diabetes.
CONCLUSIONS
Low circulating levels of sex hormone–binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.
doi:10.1056/NEJMoa0804381
PMCID: PMC2774225  PMID: 19657112
11.  An Angiotensin II (Ang II) Type 1 Receptor Blocker, Telmisartan, Improves Insulin Resistance in KK-Ay Diabetic Mice 
Metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of diabetes and cardiovascular disease (CVD) in hypertensive patients. Further, recently, the interruption of the RAS has been shown to prevent the onset of diabetes in hypertensive patients. However, whether telmisartan, an angiotensin II type 1 receptor blocker (ARB) with selective peroxisome proliferator-activated receptor-γ (PPAR-γ) agonistic property could improve insulin sensitivity is not fully understood. In this study, we studied the effects of telmisartan on insulin sensitivity in KK-Ay mice, an obese type 2 diabetic animal. Although there was no significant difference in body weight, food consumption, and glucose levels between the two groups, plasma insulin, triglycerides and non-esterified fatty acid levels were significantly decreased in telmisartan-treated KK-Ay mice, compared with control KK-Ay mice. The present findings suggest that telmisartan could exert a beneficial effect on insulin sensitivity in diabetic animals. Inhibition of the RAS by telmisartan, a selective agonist of PPAR-γ, may become a promising strategy for the treatment of hypertensive patients with metabolic syndrome and/or insulin resistance.
PMCID: PMC3614650  PMID: 23675001
telmisartan; insulin resistance; hypertension; diabetes; PPAR-γ
12.  Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes 
Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.
doi:10.1038/nrm2391
PMCID: PMC2886982  PMID: 18401346
13.  The metabolic cost of lowering blood pressure with hydrochlorothiazide 
Background
The landmark Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) placed a new spotlight on thiazide diuretics as the first-line therapy for hypertension. This is concerning as thiazide-diuretics may contribute to comorbidities associated with the current epidemic of obesity. Previous randomized clinical trials have linked thiazide diuretic treatment to insulin resistance, metabolic syndrome, and increased incidence of type 2 diabetes.
Methods
This proof of concept, longitudinal, randomized, double–blind study evaluated the effects of the angiotensin II receptor blocker Valsartan and the specific thiazide diuretic Hydrochlorothiazide (HCTZ) on hepatic triglyceride level (primary outcome), as well as triglyceride levels within other organs including the heart, skeletal muscle, and pancreas. Additionally, we evaluated whether myocardial function, insulin sensitivity, and insulin secretion were affected by these treatments.
Results
Hepatic TG levels increased by 57% post HCTZ treatment: ∆hTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: ∆hTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: ∆SI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: ∆SI V = 1.24. Treatment-induced changes in hepatic TG levels and insulin sensitivity were statistically significant between groups (phTG = 0.0098 and pSI = 0.0345 respectively). Disposition index, DI, remained unchanged after HCTZ treatment: ∆DI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: ∆DI V =1018). However, the change between groups was not statistically significant. Both therapies did not modify abdominal visceral and subcutaneous fat mass as well as myocardial structure and function. Additionally, myocardial, pancreatic, and skeletal muscle triglyceride deposits remained unchanged in both therapeutic arms.
Conclusions
Our findings are two-fold and relate to hepatic steatosis and insulin sensitivity. HCTZ treatment worsened hepatic steatosis measured as hepatic triglyceride content and reduced insulin sensitivity. Valsartan treatment did not affect hepatic triglyceride levels and improved insulin sensitivity. The results of this study reinforce the message that in patients at risk for type 2 diabetes it is particularly important to choose an antihypertensive regimen that lowers blood pressure without exacerbating patient’s metabolic profile.
doi:10.1186/1758-5996-5-35
PMCID: PMC3711837  PMID: 23837919
Type 2 diabetes; Valsartan; Hydrochlorothiazide; Proton magnetic resonance spectroscopy; Insulin sensitivity; Insulin secretion
14.  FoxO1 integrates insulin signaling to VLDL production 
Cell cycle (Georgetown, Tex.)  2008;7(20):3162-3170.
Very low-density lipoproteins (VLDL) are triglyceride-rich particles. VLDL is synthesized in hepatocytes and secreted from the liver in a pathway that is tightly regulated by insulin. Hepatic VLDL production is stimulated in response to reduced insulin action, resulting in increased release of VLDL into the blood under fasting conditions. Circulating VLDL serves as a vehicle for transporting lipids to peripheral tissues for energy homeostasis. Conversely, hepatic VLDL production is suppressed in response to increased insulin release after meals. This effect is critical for preventing prolonged excursion of postprandial plasma lipid profiles in normal individuals. In subjects with obesity and type 2 diabetes, the ability of insulin to regulate VLDL production becomes impaired due to insulin resistance in the liver, resulting in excessive VLDL secretion and accumulation of triglyceride-rich particles in the blood. Such abnormality in lipid metabolism characterizes the pathogenesis of hypertriglyceridemia and accounts for increased risk of coronary artery disease in obesity and type 2 diabetes. Nevertheless, the molecular basis that links insulin resistance to VLDL overproduction remains poorly understood. Our recent studies illustrate that the forkhead transcription factor FoxO1 acts in the liver to integrate hepatic insulin action to VLDL production. Augmented FoxO1 activity in insulin resistant livers promotes hepatic VLDL overproduction and predisposes to the development of hypertriglyceridemia. These new findings raise an important question: Is FoxO1 a therapeutic target for ameliorating hypertriglyceridemia? Here we discuss this question in the context of recent advances toward our understanding of the pathophysiology of hypertriglyceridemia.
PMCID: PMC2664837  PMID: 18927507
hypertriglyceridemia; FoxO1; MTP; ApoB; VLDL
15.  Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes 
Human Molecular Genetics  2009;19(3):535-544.
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
doi:10.1093/hmg/ddp522
PMCID: PMC2798726  PMID: 19933169
16.  Apolipoprotein C3 Gene Variants in Nonalcoholic Fatty Liver Disease 
The New England journal of medicine  2010;362(12):1082-1089.
BACKGROUND
Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown.
METHODS
In 95 healthy Asian Indian men, a group known to have a high prevalence of non-alcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non–Asian Indian men.
RESULTS
Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non–Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease.
CONCLUSIONS
The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.
doi:10.1056/NEJMoa0907295
PMCID: PMC2976042  PMID: 20335584
17.  The Role of Testosterone in the Etiology and Treatment of Obesity, the Metabolic Syndrome, and Diabetes Mellitus Type 2 
Journal of Obesity  2010;2011:471584.
Obesity has become a major health problem. Testosterone plays a significant role in obesity, glucose homeostasis, and lipid metabolism. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis, and cardiovascular morbidity and mortality. The main components of the syndrome are visceral obesity, insulin resistance, glucose intolerance, raised blood pressure and dyslipidemia (elevated triglycerides, low levels of high-density lipoprotein cholesterol), and a proinflammatory and thrombogenic state. Cross-sectional epidemiological studies have reported a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin (SHBG) predict a higher incidence of the metabolic syndrome. Administration of testosterone to hypogonadal men reverses part of the unfavorable risk profile for the development of diabetes and atherosclerosis.
doi:10.1155/2011/471584
PMCID: PMC2931403  PMID: 20847893
18.  PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans 
The Journal of Clinical Investigation  2011;121(6):2504-2517.
C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.
doi:10.1172/JCI46045
PMCID: PMC3104767  PMID: 21576825
19.  Hyperglycemia and a Common Variant of GCKR Are Associated With the Levels of Eight Amino Acids in 9,369 Finnish Men 
Diabetes  2012;61(7):1895-1902.
We investigated the association of glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes with amino acid levels in the population-based Metabolic Syndrome in Men (METSIM) Study, including 9,369 nondiabetic or newly diagnosed type 2 diabetic Finnish men. Plasma levels of eight amino acids were measured with proton nuclear magnetic resonance spectroscopy. Increasing fasting and 2-h plasma glucose levels were associated with increasing levels of several amino acids and decreasing levels of histidine and glutamine. Alanine, leucine, isoleucine, tyrosine, and glutamine predicted incident type 2 diabetes in a 4.7-year follow-up of the METSIM Study, and their effects were largely mediated by insulin resistance (except for glutamine). We also found significant correlations between insulin sensitivity (Matsuda insulin sensitivity index) and mRNA expression of genes regulating amino acid degradation in 200 subcutaneous adipose tissue samples. Only 1 of 43 risk single nucleotide polymorphisms for type 2 diabetes or hyperglycemia, the glucose-increasing major C allele of rs780094 of GCKR, was significantly associated with decreased levels of alanine and isoleucine and elevated levels of glutamine. In conclusion, the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia, reflecting, at least in part, insulin resistance. Only one single nucleotide polymorphism regulating hyperglycemia was significantly associated with amino acid levels.
doi:10.2337/db11-1378
PMCID: PMC3379649  PMID: 22553379
20.  Early Emergence of Ethnic Differences in Type 2 Diabetes Precursors in the UK: The Child Heart and Health Study in England (CHASE Study) 
PLoS Medicine  2010;7(4):e1000263.
Peter Whincup and colleagues carry out a cross-sectional study examining ethnic differences in precursors of of type 2 diabetes among children aged 9–10 living in three UK cities.
Background
Adults of South Asian origin living in the United Kingdom have high risks of type 2 diabetes and central obesity; raised circulating insulin, triglyceride, and C-reactive protein concentrations; and low HDL-cholesterol when compared with white Europeans. Adults of African-Caribbean origin living in the UK have smaller increases in type 2 diabetes risk, raised circulating insulin and HDL-cholesterol, and low triglyceride and C-reactive protein concentrations. We examined whether corresponding ethnic differences were apparent in childhood.
Methods and Findings
We performed a cross-sectional survey of 4,796 children aged 9–10 y in three UK cities who had anthropometric measurements (68% response) and provided blood samples (58% response); ethnicity was based on parental definition. In age-adjusted comparisons with white Europeans (n = 1,153), South Asian children (n = 1,306) had higher glycated haemoglobin (HbA1c) (% difference: 2.1, 95% CI 1.6 to 2.7), fasting insulin (% difference 30.0, 95% CI 23.4 to 36.9), triglyceride (% difference 12.9, 95% CI 9.4 to 16.5), and C-reactive protein (% difference 43.3, 95% CI 28.6 to 59.7), and lower HDL-cholesterol (% difference −2.9, 95% CI −4.5 to −1.3). Higher adiposity levels among South Asians (based on skinfolds and bioimpedance) did not account for these patterns. Black African-Caribbean children (n = 1,215) had higher levels of HbA1c, insulin, and C-reactive protein than white Europeans, though the ethnic differences were not as marked as in South Asians. Black African-Caribbean children had higher HDL-cholesterol and lower triglyceride levels than white Europeans; adiposity markers were not increased.
Conclusions
Ethnic differences in type 2 diabetes precursors, mostly following adult patterns, are apparent in UK children in the first decade. Some key determinants operate before adult life and may provide scope for early prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and the number of people affected by this chronic disease is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood sugar levels rise after eating (digestion of food produces glucose). In people with type 2 diabetes (the most common type of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become less responsive to insulin (insulin resistant). Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. Long-term complications of diabetes include kidney failure, blindness, nerve damage, and an increased risk of developing cardiovascular problems, including heart disease and stroke.
Why Was This Study Done?
South Asians and African-Caribbeans living in Western countries tend to have higher rates of type 2 diabetes than host populations. South Asian adults living in the UK, for example, have a 3-fold higher risk of developing type 2 diabetes than white Europeans. They also have higher fasting blood levels of glucose, insulin and triglycerides (a type of fat), higher blood levels of “glycated hemoglobin” (HbA1c; an indicator of average of blood-sugar levels over time), more body fat (increased adiposity), raised levels of a molecule called C-reactive protein, and lower levels of HDL-cholesterol (another type of fat) than white Europeans. Most of these “diabetes precursors” (risk factors) are also seen in black African-Caribbean adults living in the UK except that individuals in this ethnic group often have raised HDL-cholesterol levels and low triglyceride levels. Ethnic differences in type 2 diabetes precursors are also present in adolescents, but the extent to which they are present in childhood remains unclear. Knowing this information could have implications for diabetes prevention. In this population-based study, therefore, the researchers investigate patterns of diabetes precursors in 9- to 10-year-old UK children of white European, South Asian, and black African-Caribbean origin.
What Did the Researchers Do and Find?
The researchers enrolled nearly 5,000 children (including 1,153 white European, 1,306 South Asian and 1,215 black African-Caribbean children) from primary schools with high prevalences of ethnic minority pupils in London, Birmingham, and Leicester in the Child Heart and Health study in England (CHASE). They measured and weighed more than two-thirds of the enrolled children and determined their adiposity. They also took blood samples for measurement of diabetes precursors from nearly two-thirds of the children. The recorded ethnicity of each child was based on parental definition. The researchers' analysis of these data showed that, compared with white Europeans, South Asian children had higher levels of HbA1c, insulin, triglycerides, and C-reactive protein but lower HDL-cholesterol levels. In addition, they had higher adiposity levels than the white European children, but this did not account for the observed differences in the other diabetes precursors. Black African-Caribbean children also had higher levels of HbA1c, insulin, and C-reactive protein than white European children, although the differences were smaller than those between South Asians and white Europeans. Similar to black African-Caribbean adults, however, children of this ethnic origin had higher HDL-cholesterol and lower triglyceride levels than white Europeans.
What Do These Findings Mean?
These findings indicate that ethnic differences in diabetes precursors are already present in apparently healthy children before they are 10 years old. Furthermore, most of the ethnic differences in diabetes precursors seen among the children follow the pattern seen in adults. Although these findings need confirming in more children, they suggest that the ethnic differences in type 2 diabetes susceptibility first described in immigrants to the UK are persisting in UK-born South Asian and black African-Caribbean children. Most importantly, these findings suggest that some of the factors thought to be responsible for ethnic differences in type 2 diabetes—for example, varying levels of physical activity and dietary differences—are operating well before adult life. Interventions that target these factors early could, therefore, offer good opportunities for diabetes prevention in high-risk ethnic groups, provided such interventions are carefully tailored to the needs of these groups.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000263.
The International Diabetes Federation provides information about all aspects of diabetes (in English, French and Spanish)
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals and the general public, including information on diabetes in specific US populations (in English and Spanish)
The UK National Health Service also provides information for patients and carers about type 2 diabetes (in several languages)
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
The US Agency for Healthcare Research and Quality has a fact sheet on diabetes disparities among racial and ethnic minorities
doi:10.1371/journal.pmed.1000263
PMCID: PMC2857652  PMID: 20421924
21.  Intracerebroventricular Leptin Infusion Improves Glucose Homeostasis in Lean Type 2 Diabetic MKR Mice via Hepatic Vagal and Non-Vagal Mechanisms 
PLoS ONE  2011;6(2):e17058.
MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.
doi:10.1371/journal.pone.0017058
PMCID: PMC3040739  PMID: 21379576
22.  Three-year increase of gamma-glutamyltransferase level and development of type 2 diabetes in middle-aged men and women: the D.E.S.I.R. cohort 
Diabetologia  2006;49(11):2599-2603.
Aims/Hypothesis
Among hepatic markers, gamma-glutamyltransferase (GGT) is the main predictor for the development of type 2 diabetes, but there is no data on GGT change and type 2 diabetes incidence.
Methods
Data at baseline and at three years from the D.E.S.I.R. cohort were used: 2071 men and 2130 women without baseline diabetes.
Results
Change in GGT level was correlated with changes in markers of insulin-resistance (fasting insulin, HOMA index) as well as with elements of the metabolic syndrome: fasting glucose, central obesity, triglycerides, systolic and diastolic blood pressure. The three-year increase in GGT was associated with incident type 2 diabetes, in both sexes, after adjusting for age and baseline GGT. After further adjustment for baseline confounding factors including alanine-aminotransferase, alcohol intake, overall and central obesity, the odds ratios (95% Cl) for incident type 2 diabetes associated with an increase compared to a decrease in GGT level were 2.54 (1.38–4.68) in men (p<0.003) and 2.78 (1.20–6.42) in women (p<0.02). These associations were slightly attenuated after adjusting for the 3-year change in BMI, alcohol consumption, fasting insulin: 2.49 (1.28–4.86) in men and 2.53 (1.01–6.40) in women. This relationship was not dependent on intra-individual variability.
Conclusions
An increase in GGT level over time, even when GGT is in the normal range, is correlated with increasing insulin resistance and is associated with a risk of incident type 2 diabetes in both sexes, independently of baseline GGT, which is itself a diabetes risk factor.
doi:10.1007/s00125-006-0418-x
PMCID: PMC1975686  PMID: 16969645
Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; blood; enzymology; epidemiology; Female; France; epidemiology; Humans; Insulin; blood; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Risk Factors; Sex Characteristics; gamma-Glutamyltransferase; blood
23.  Farnesoid X receptor is essential for normal glucose homeostasis 
Journal of Clinical Investigation  2006;116(4):1102-1109.
The bile acid receptor farnesoid X receptor (FXR; NR1H4) is a central regulator of bile acid and lipid metabolism. We show here that FXR plays a key regulatory role in glucose homeostasis. FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance. Their insulin resistance was confirmed by the hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. In FXR–/– skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue. In contrast to the results in FXR–/– mice, bile acid activation of FXR in WT mice repressed expression of gluconeogenic genes and decreased serum glucose. The absence of this repression in both FXR–/– and small heterodimer partner–null (SHP–/–) mice demonstrated that the previously described FXR-SHP nuclear receptor cascade also targets glucose metabolism. Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade.
doi:10.1172/JCI25604
PMCID: PMC1409738  PMID: 16557297
24.  Plasma glycosylphosphatidylinositol-specific phospholipase D predicts the change in insulin sensitivity in response to a low fat but not a low carbohydrate diet in obese women 
Metabolism: clinical and experimental  2008;57(4):10.1016/j.metabol.2007.11.007.
Context
Although circulating glycosylphosphatidylinositol-specific phospholipase D, a minor high density lipoprotein-associated protein, is elevated in patients with insulin resistance or high triglycerides, no information is available on the effect of weight loss or changes in insulin sensitivity on circulating glycosylphosphatidylinositol-specific phospholipase D levels.
Objective
Determine the effect of weight loss and changes in insulin sensitivity on plasma glycosylphosphatidylinositol-specific phospholipase D levels.
Participants
Forty two non-diabetic obese women.
Intervention
Three month dietary intervention randomizing patients to a low fat or a low carbohydrate diet.
Main outcome measures
Plasma glycosylphosphatidylinositol-specific phospholipase D levels and insulin sensitivity as estimated by the homeostasis model assessment.
Results
The very low carbohydrate diet group lost more weight after 3 months (−7.6 ± 3.2 vs. −4.2 ± 3.5 kg, P < 0.01) although the decrease in insulin resistance was similar between groups. Weight loss with either diet did not alter plasma glycosylphosphatidylinositol-specific phospholipase D levels. However, baseline glycosylphosphatidylinositol-specific phospholipase D levels correlated with the change in insulin sensitivity in response to the low fat diet while baseline insulin sensitivity correlated the change in insulin sensitivity in response to the low carbohydrate diet.
Conclusions
Plasma GPI-PLD may serve as a clinical tool to determine the effect of a low fat diet on insulin sensitivity.
doi:10.1016/j.metabol.2007.11.007
PMCID: PMC3857163  PMID: 18328347
glycosylphosphatidylinositol phospholipase D; diet; obesity; insulin sensitivity; women
25.  Overexpression of apolipoprotein A5 in mice is not protective against body weight gain and aberrant glucose homeostasis 
Apolipoprotein A5 [APOA5] is expressed primarily in the liver and modulates plasma triglyceride levels in mice and humans. Mice overexpressing APOA5 exhibit reduced plasma triglyceride levels. Since there is a tight association between plasma triglyceride concentration and traits of the metabolic syndrome, we utilized transgenic mice overexpressing human APOA5 to test the concept that these mice would be protected from diet-induced obesity and insulin resistance. Male and female transgenic and wild-type mice on the FVB/N genetic background were fed standard rodent chow or a diet rich in fat and sucrose for 18 weeks during which time clinical phenotypes associated with obesity and glucose homeostasis were measured. We found that APOA5 transgenic (A5tg) mice were resistant to diet induced changes in plasma triglyceride but not total cholesterol levels. Body weights were similar between the genotypes for females and males, although male A5tg mice showed a modest but significant increase in the relative size of inguinal fat pads. Although male A5tg mice showed a significantly increased ratio of plasma insulin to glucose, profiles of glucose clearance as evaluated following injections of glucose or insulin failed to reveal any differences between genotypes. Overall, our data showed that there was no advantage to responses to diet-induced obesity with chronic reduction of plasma triglyceride levels as mediated by overexpression of APOA5.
doi:10.1016/j.metabol.2008.11.018
PMCID: PMC2689095  PMID: 19303979
APOA5; mice; obesity; triglyceride; glucose tolerance

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