Prominent publications by David Bousfield Savage

KOL Index score: 17885

Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near ...

Also Ranks for: Type 2 Diabetes |  lowering genetic |  density lipoprotein |  coronary artery disease |  ldl risk
KOL Index score: 14797

Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively ...

Also Ranks for: Antisense Oligonucleotides |  induced hepatic |  dgat1 dgat2 |  diacylglycerol acyltransferase |  insulin resistance
KOL Index score: 13350

Importance: Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown.

Objective: To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their ...

Also Ranks for: Genetic Variants |  2 diabetes |  higher whr |  abdominal fat |  cardiovascular risk
KOL Index score: 12946

Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and ...

Also Ranks for: Hepatic Insulin Resistance |  acc1 acc2 |  fat oxidation |  coa carboxylase |  antisense oligonucleotides
KOL Index score: 12788

Importance: Pharmacological enhancers of lipoprotein lipase (LPL) are in preclinical or early clinical development for cardiovascular prevention. Studying whether these agents will reduce cardiovascular events or diabetes risk when added to existing lipid-lowering drugs would require large outcome trials. Human genetics studies can help prioritize or deprioritize these resource-demanding endeavors.

Objective: To investigate the independent and combined associations of genetically ...

Also Ranks for: 2 Diabetes |  lipoprotein lipase |  lowering alleles |  lower risk |  ldl coronary
KOL Index score: 12626

BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.

METHODS AND FINDINGS: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The ...

Also Ranks for: Type 2 Diabetes |  genetic predisposition |  chain amino |  bcaa levels |  impaired metabolism
KOL Index score: 11470

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial ...

Also Ranks for: Desaturase Activity |  peroxisome proliferator |  activated receptor |  fatty acid |  insulin sensitivity
KOL Index score: 11426

Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2(-/-) and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2(-/-) and WT control ...

Also Ranks for: Fat Oxidation |  insulin sensitivity |  coa carboxylase |  knockout muscle |  energy expenditure
KOL Index score: 11080

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to ...

Also Ranks for: Insulin Resistance |  body fat |  type 2 |  genetic variants |  obese individuals
KOL Index score: 10782

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show—in two independent randomized controlled clinical trials—that metformin increases circulating levels of the peptide hormone growth/differentiation ...

Also Ranks for: Energy Balance |  metformin body weight |  circulating levels |  gdf15 effects |  highfat diet
KOL Index score: 10776

Recent studies in murine models suggest that resistin (also called Fizz3 [1]), a novel cysteine-rich protein secreted by adipocytes, may represent the long-sought link between obesity and insulin resistance (2). Furthermore, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists appear to inhibit resistin expression in murine adipocytes, providing a possible explanation for the mode of action of this class of insulin sensitizers (2). Using a fluorescent real-time reverse ...

Also Ranks for: Ectopic Humans |  resistin mrna |  messenger receptors |  activated receptor |  proteins male
KOL Index score: 10766

BACKGROUND: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.

METHODS: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early ...

Also Ranks for: Endometrial Cancer |  mendelian randomization |  causal association |  2 diabetes |  fasting insulin
KOL Index score: 10541

We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, ...

Also Ranks for: Insulin Resistance |  metabolic syndrome |  skeletal muscle |  plasma concentrations |  atherogenic dyslipidemia
KOL Index score: 10164

PurposeThe purpose of this study is to summarize the effectiveness and safety of metreleptin in patients with congenital or acquired generalized lipodystrophy.MethodsPatients (n = 66) aged ≥6 months had lipodystrophy, low circulating leptin, and ≥1 metabolic abnormality (diabetes mellitus, insulin resistance, or hypertriglyceridemia). Metreleptin dose (once or twice daily) was titrated to a mean dose of 0.10 mg/kg/day with a maximum of 0.24 mg/kg/day. Means and changes from baseline to ...

Also Ranks for: Generalized Lipodystrophy |  tgs month |  metreleptin patients |  liver volume |  decrease hba1c

Key People For Insulin Resistance

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David Bousfield Savage:Expert Impact

Concepts for whichDavid Bousfield Savagehas direct influence:Insulin resistance,  Severe insulin resistance,  Type 2 diabetes,  2 diabetes,  Metabolic syndrome,  Partial lipodystrophy,  Severe insulin,  Congenital lipodystrophy.

David Bousfield Savage:KOL impact

Concepts related to the work of other authors for whichfor which David Bousfield Savage has influence:Insulin resistance,  Type 2 diabetes,  Adipose tissue,  Metabolic syndrome,  Skeletal muscle,  Lipid metabolism,  Fatty liver.



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Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, CB2 0QQ, Cambridge, UK | University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabo