Search

OBJECTIVE Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.

Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole metagenome shotgun sequencing with taxonomic profiling. We examined associations between 36 butyrate-producing taxa (7 genera, 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, body mass index, and race. Genus Coprococcus was associated with higher insulin sensitivity (β=0.14, P=0.002) and disposition index (β=0.12, P=0.012) and a lower rate of dysglycemia (odds ratio 0.91, 95% confidence interval (CI) 0.85-0.97, P=0.0025); in contrast, Flavonifractor was associated with lower insulin sensitivity (β=-0.13, P=0.004) and disposition index (β=-0.11, P=0.04) and higher prevalence of dysglycemia (OR 1.22, 95% CI 1.08-1.38, P=0.0013). Species-level analyses found 10 bacteria associated with beneficial directions of effects and two bacteria with adverse associations on insulin homeostasis and dysglycemia. While most butyrate-producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria, suggesting that microbiome-directed therapeutic measures to prevent or treat diabetes should be targeted to specific butyrate-producing taxa rather than all butyrate producers.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids., The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of β-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating β-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.

The aim of this study was to test the hypothesis that plasma leptin concentrations contributed to the pathophysiology of NIDDM by decreasing both insulin-mediated glucose disposal and glucose-stimulated insulin secretion. The study was performed in 60 women with normal oral glucose tolerance. Differences in insulinmediated glucose disposal were determined by comparing the steady-state plasma glucose (SSPG) concentrations attained at the end of a 180-min constant infusion of somatostatin, glucose, and insulin, while comparisons of glucose-stimulated insulin secretion were based on the incremental increase in insulin concentration 30 min after an oral glucose challenge (ΔIns) as compared with the fasting value. The results showed that the higher the fasting plasma leptin concentration, the greater the degree of insulin resistance (r = 0.47, P < 0.01). Furthermore, multiple regression analysis indicated that the relationship between leptin and SSPG was independent of age and degree of obesity as estimated by BMI. However, since the total integrated plasma insulin response was highly correlated with both SSPG (r = 0.80, P < 0.001) and leptin (r = 0.55, P < 0.01), multiple regression analysis was repeated, adding total insulin response to the model. When this was done, the significant relationship between leptin and SSPG disappeared, whereas both BMI (P < 0.03) and insulin response (P < 0.001) were correlated with SSPG. A significant relationship between leptin and AIns was seen, but it was a positive one (r = 0.31, P < 0.02), not a negative one as would be expected if circulating levels of leptin inhibited glucose-stimulated insulin secretion. Furthermore, multiple regression analysis could only confirm an independent relationship between AIns and SSPG, but not between AIns and leptin. The results of these studies do not support the view that circulating leptin has a primary effect on either insulin action or secretion in normal female volunteers. It seems more likely that chronic hyperinsulinemia in insulin-resistant individuals acts to increase adipose tissue leptin synthesis and secretion, leading to higher ambient leptin concentrations.

The efficacy of fenofibrate (FEN), rosiglitazone (RSG), or a calorie-restricted diet (CRD) to reduce cardiovascular disease risk was compared in 37 overweight/obese, insulin resistant, nondiabetic individuals. Measurements were made of insulin sensitivity, fasting lipid and lipoprotein concentrations, and postprandial plasma glucose, insulin, free fatty acid, and triglyceride concentrations, before and after three months of treatment with FEN, RSG, or the CRD. Weight fell in the CRD group, but did not change significantly following treatment with either drug. Insulin sensitivity improved significantly in the CRD and RSG-treated groups, but to a greater extent in those given RSG, without a significant difference when comparing FEN treatment to the CRD. Total cholesterol concentrations were significantly lower following FEN and CRD. Fasting plasma triglyceride concentrations decreased significantly in FEN-treated and CRD groups, but postprandial concentrations decreased only in the FEN-treated subjects. Significant decreases in postprandial glucose and insulin concentrations were only seen in the RSG-treated and CRD groups. FEN administration improved the dyslipidemia in these subjects, without changing insulin sensitivity, whereas insulin sensitivity was enhanced in RSG-treated patients, without improvement in the dyslipidemia. Weight loss in the CRD group led to improvements in both insulin sensitivity and dyslipidemia, but the change in the former was less than in RSG-treated individuals, and the improvement in lipid metabolism not as great as with administration of FEN. In conclusion, there does not appear to be one therapeutic intervention that effectively treats all the metabolic abnormalities present in these patients at greatly increased risk of cardiovascular disease.

The ability of spontaneous running to prevent carbohydrate-induced hypertriglyceridemia was studied in young, nonobese rats. Exercise-trained and sedentary rats were fed a diet consisting of (as percent total calories) 12% fat, 22% protein, and 66% carbohydrate. The source of the carbohydrate was varied, and experiments were carried out with sucrose and glucose as the sole dietary carbohydrate. Plasma triglyceride (TG) levels rose in response to both forms of dietary carbohydrate in both sedentary and exercise-trained rats, but the magnitude of the elevation was greatly attenuated in the exercise-trained group. Plasma insulin concentrations were also significantly lower in exercise-trained rats. Measurements of hepatic very low density lipoprotein (VLDL)-TG secretion rate and adipose tissue lipoprotein lipase (LPL) activity were made in an effort to determine how exercise-training prevented the development of carbohydrate-induced hypertriglyceridemia. The results of these studies indicated that perfused livers of exercise-trained rats secreted significantly less VLDL-TG, whereas adipose tissue LPL activity of the two groups was similar. On the basis of these results, it is postulated that the ability of exercise-training to inhibit carbohydrate-induced hypertriglyceridemia is due to an increase in insulin sensitivity resulting from chronic exercise. As a result, the postprandial insulin responses to high carbohydrate diets would be relatively reduced in exercise-trained rats, leading to decreased hepatic VLDL-TG secretion, and lower plasma triglyceride concentrations.

The lipid-laden foam cells from atherosclerotic lesions appear to be derived from macrophages which have accumulated lipids from plasma lipoproteins. When examined in vitro, thioglycolate-elicited mouse peritoneal macrophages do not accumulate lipids when exposed to normal low density lipoproteins (LDL), but take up very low density lipoproteins (VLDL) or chemically modified LDL with resultant lipid accumulation. Patients with noninsulin-dependent diabetes mellitus (NIDDM) have an increased incidence of atherosclerosis, due in part to disturbances in lipoprotein metabolism. We investigated the possibility that VLDL isolated from patients with NIDDM are taken up by mouse peritoneal macrophages more avidly than normal. Two groups of patients with NIDDM were studied; one group was normotriglyceridemic and the other group was hypertriglyceridemic. The VLDL from both normotriglyceridemic and hypertriglyceridemic patients were enriched in cholesterol and triglyceride compared to that from normal subjects. Thioglycolate-elicited mouse peritoneal macrophages bound and degraded greater amounts of VLDL isolated from patients with NIDDM (both normo- and hypertriglyceridemic) than of VLDL from normal subjects. While normal VLDL caused a marked increase in cellular triglyceride and cholesteryl ester contents in macrophages, VLDL isolated from patients with NIDDM resulted in an even greater cellular accumulation of lipids. These results suggest that the VLDL of patients with NIDDM have alterations in their composition and metabolic behavior. The increased uptake of VLDL by macrophages may contribute to the enhanced atherosclerosis present in NIDDM.

The relationship between total and heparin-releasable adipose tissue lipoprotein lipase (LPL) activity and very low density lipoprotein (VLDL0-triglyceride (TG) removal rate was studied in normal rats. Significant variation in both total and heparin-releasable adipose tissue LPL activity could be induced by changing diet and/or time of day at which the measurements were made. However, these maneuvers did not seem to modify VLDL-TG kinetics, and substantial variations (both increases and decreases) in LPL activity could be produced without altering VLDL-TG removal. These data indicate that quantitative variations in adipose tissue LPL activity as directly measured do not give rise to useful insights into VLDL-TG kinetics.

Questions have been raised as to whether reduced lipoprotein lipase (LPL) activity can account for the defect in plasma removal of very low density lipoprotein (VLDL) associated with insulin deficiency. In order to study this issue, streptozotocin-induced insulin deficiency was produced in 2-mo-old rats. Three groups of rats were studied: control, moderate diabetes (glucose > 200 < 350 mg/dl), and severe diabetes (glucose > 350 mg/dl). One week later food was withdrawn at 8 a.m., and the following measurements made at 2 p.m. (6 h after removal of food): (1) plasma glucose, insulin, and triglyceride (TG) levels; (2) VLDL-TG secretion rate; and (3) adipose tissue and skeletal muscle LPL activity. Rats with moderate diabetes had higher glucose and lower insulin levels than did control rats, and these differences were accentuated in rats with severe diabetes. Plasma TG levels were elevated (P < 0.001) in rats with moderate (↑99%) and severe diabetes (↑126%), and this was associated with a fall (P < 0.001) in VLDL-TG secretion. An increase in plasma TG levels, despite a decrease in VLDL-TG secretion, indicates the presence of a profound defect in VLDL-TG removal from plasma. However, muscle LPL of rats with severe diabetes and moderate diabetes was equal to that of control rats, and adipose tissue LPL was only moderately (P < 0.05) reduced (MD = ↓25%, SD = ↓32%). These results indicate that plasma TG levels rise in young, insulin-deficient rats as a result of a defect in removal of VLDL-TG from plasma. This removal defect is associated with normal muscle and only moderately reduced adipose tissue LPL activity, suggesting that the VLDL-TG removal defect associated with insulin deficiency may not be a simple function of a decrease in total (muscle + adipose tissue) LPL activity.

Previously, we indicated that luteal cells from colchicine-treated superovulatory (luteinized) rats show decreased capacity for progesterone production. The current study investigates the possibility that colchicine exerts this effect by interfering with the mechanism by which cholesterol is processed and/or synthesized by luteal cells. To this end, animals were treated with saline or colchicine after which the luteinized ovary or isolated luteal cells were assayed for their cholesterol content, their ability to synthesize cholesterol endogenously, or their ability to utilize lipoprotein-delivered cholesterol for the production of progesterone. The results show that animals treated with colchicine show a number of changes in luteal cell cholesterol metabolism: namely a 60% decline in stored cholesterol, a 3-fold rise in the activity of the cholesterol synthesizing enzyme HMG CoA reductase (although no change occurs in other cholesterol metabolizing enzymes), and a 3-fold rise in the capacity of the cells to incorporate precursor [14C]acetate into cholesterol. On the other hand, cells of animals treated with colchicine or cells treated with colchicine under in vitro circumstances are unable to fully utilize cholesterol provided by high density lipoproteins (HDL): this occurs despite the fact that the binding of HDL particles to luteal cells is quite normal after colchicine treatment. These findings are consistent with the view that a primary effect of colchicine on luteal cell progesterone production is in preventing the normal uptake of HDL-cholesterol.

Rats were fed diets containing (as percent of calories) 66% glucose or fructose, 22% casein, and 12% lard, for 1 wk. The effects of these diets on plasma triglyceride, glucose, and insulin concentrations were compared to those of control rats eating regular rat chow. Plasma triglyceride levels increased from a mean (+/- SE) control level of 85 +/- 7 to 142 +/- 9 (p less than 0.001) and 380 +/- 38 (p less than 0.001) mg/dl in dextrose- and fructose-fed rats, respectively. Plasma insulin concentrations demonstrated a similar increase, rising from a mean (+/- SE) control value of 29 +/- 4 microunits/ml to 55 +/- 10 microunits/ml in dextrose-fed rats and 85 +/- 12 microunits/ml in rats eating the fructose diet. Plasma glucose concentrations of the three groups were comparable. These results indicate that fructose-induced hypertriglyceridemia is associated with significant hyperinsulinemia.