Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes.

CONTEXT: Pancreatic atrophy is common in longstanding type 1 diabetes, but there are limited data concerning pancreas size at diagnosis. OBJECTIVE: Our objective was to determine whether pancreatic size was reduced in patients with recently diagnosed type 1 diabetes and assess whether pancreatic volume was related to residual ß-cell function or islet autoantibodies. DESIGN AND SETTING: We conducted a controlled cohort study with strict inclusion criteria, recruiting from hospital diabetes clinics between 2007 and 2010. PATIENTS AND HEALTHY CONTROLS: Participants included 20 male adult patients (median age 27 yr) with recent-onset type 1 diabetes (median duration 3.8 months) and 24 male healthy controls (median age 27 yr). INTERVENTION: Interventions included noninvasive magnetic resonance imaging, collection of fasting blood samples, and glucagon stimulation testing in patients. MAIN OUTCOME MEASURES: We compared pancreatic volume estimates between patients with recent-onset type 1 diabetes and healthy controls as planned a priori. RESULTS: Scans were analyzed by an experienced radiologist blinded to diabetes status. Pancreatic volume correlated with body weight in patients and controls (P = 0.007). After adjustment for body weight, mean pancreatic volume index was 26% less in patients (1.19 ml/kg, se 0.07 ml/kg) than in controls (1.61 ml/kg, se 0.08 ml/kg) (P = 0.001). No correlation was seen between pancreatic volume index in patients and diabetes duration, glucose or C-peptide levels, glycated hemoglobin, and islet autoantibodies. CONCLUSIONS: Pancreatic volume is reduced by 26% in patients with type 1 diabetes within months of diagnosis, suggesting that atrophy begins years before the onset of clinical disease. Pancreatic atrophy within individuals is therefore a potential clinical marker of disease progression.

Parallel activation of de novo lipogenesis and stearoyl-CoA desaturase activity after 3 d of high-carbohydrate feeding.

BACKGROUND: High-carbohydrate (HC) diets increase de novo lipogenesis (DNL), but effects on stearoyl-CoA desaturase (SCD) are not so well studied. OBJECTIVE: The objective was to investigate DNL and SCD in liver and adipose tissue by using fatty acid ratios after short-term dietary intervention. DESIGN: Eight subjects consumed isoenergetic 3-d HC (10% fat; 75% carbohydrates) or higher fat (HF; 40% fat; 45% carbohydrates) diets (sugar to starch ratio: 60:40 for both) in a crossover study. Blood was taken from an artery and a vein draining subcutaneous adipose tissue. DNL and SCD activity were investigated by using the ratios of 16:0 to 18:2n-6 and of 16:1n-7 to 16:0, respectively. A test meal, including [U-(13)C]palmitate was given to trace dietary fatty acid incorporation into VLDL-triacylglycerol (TG). The conversion of intravenously infused [(2)H(2)]palmitic acid to [(2)H(2)]palmitoleic acid in VLDL-TG was quantified as a specific marker of hepatic SCD activity. RESULTS: The VLDL-TG 16:0/18:2n-6 ratio, which reflects hepatic DNL, was greater after the HC diet than after the HF diet (P = 0.02). With the HC diet, increased plasma TG concentrations correlated with 16:0/18:2n-6 ratios (r = 0.76, P = 0.028). Plasma VLDL-TG and adipose venous nonesterified fatty acid (NEFA) 16:1n-7/16:0 ratios were higher after the HC diet (fasting: P = 0.01 and P = 0.05, respectively; postprandial: P = 0.03 and P = 0.05, respectively). Changes in fasting VLDL-TG 16:0/18:2n-6 and 16:1n-7/16:0 ratios were associated (P = 0.06). The contribution of total fatty acids from splanchnic sources (including DNL) was higher after the HC diet (P = 0.02). Expression of lipogenic genes in subcutaneous adipose tissue was not significantly affected by diet. CONCLUSION: Parallel activation of DNL and SCD was found after a short period of HC feeding.

Reduced oxidation of dietary fat after a short term high-carbohydrate diet.

BACKGROUND: Short-term high-carbohydrate (HC) diets induce metabolic alterations, including hypertriacylglycerolemia, in both the fasting and postprandial states. The underlying tissue-specific alterations in fatty acid metabolism are not well understood. OBJECTIVE: We investigated alterations in exogenous and endogenous fatty acid metabolism by using stable isotope tracers to label meal triacylglycerol and plasma fatty acids. DESIGN: Eight healthy subjects consumed isocaloric diets containing a high percentage of energy from carbohydrates or a higher percentage of energy from fat for 3 d in a randomized crossover dietary intervention study. A test meal containing [U-13C] palmitate was combined with intravenous infusion of [2H2] palmitate to label plasma fatty acids and VLDL triacylglycerol. Blood and breath samples were taken before the meal and for 6 h postprandially. Blood samples were drawn from the femoral artery and from veins draining subcutaneous adipose tissue and forearm muscle for monitoring of tissue-specific metabolic substrate partitioning. RESULTS: Systemic triacylglycerol concentrations were increased in both fasting (P = 0.02) and postprandial (P = 0.02) periods, and a greater amount of infused labeled fatty acid appeared in VLDL triacylglycerol after the HC diet than after the higher-fat diet (P = 0.05). Significantly less 13CO2 was exhaled after the HC diet (P = 0.04) and significantly less production of 13CO2 was seen across forearm muscle (P = 0.04). Systemic 3-hydroxybutyrate was significantly lower, postprandially, after the HC diet (P = 0.02). CONCLUSION: Metabolic alterations suggestive of repartitioning of fatty acids away from oxidation toward esterification in both liver and muscle occur in response to short-term adaptation to a HC diet.

The contribution of splanchnic fat to VLDL triglyceride is greater in insulin-resistant than insulin-sensitive men and women: studies in the postprandial state.

OBJECTIVE: We aimed to determine differences in the postprandial contributions of different fatty acid sources to VLDL triglycerides (TGs) in healthy men and women with varying degrees of insulin resistance. RESEARCH DESIGN AND METHODS: Insulin-resistant (n = 11) and insulin-sensitive (n = 11) men and women (n = 6) were given an intravenous infusion of [(2)H(2)]palmitic acid to investigate systemic nonesterified fatty acid (NEFA) incorporation into VLDL TGs. Participants were also fed a mixed meal containing [U-(13)C]palmitic acid to investigate the contribution of dietary fatty acids to VLDL TG production. Blood samples were taken over the following 6 h. Separation of VLDL was performed by density gradient ultracentrifugation and immunoaffinity techniques specific to apolipoprotein B-100. RESULTS: Insulin-resistant and insulin-sensitive men had similar postprandial chylomicron and chylomicron remnant TG concentrations, but insulin-resistant men had higher postprandial VLDL TG concentrations (median [range]; area under the curve 485 micromol/l [123-992] vs. 287 micromol/l [162-510]; P < 0.05). At 360 min, most of the difference in VLDL TGs was accounted for by an additional contribution from splanchnic fat (means +/- SE; 331 +/- 76 micromol/l vs. 89 +/- 25 micromol/l; P < 0.01). The contribution of fatty acids from endogenous systemic NEFAs was similar across the groups, as were dietary fatty acids. There was no difference in the VLDL TG concentration or the contribution of different fatty acid sources between insulin-sensitive men and women. CONCLUSIONS: In the postprandial period, the only sources of fatty acids for VLDL TG production to differ in the insulin-resistant compared with the insulin-sensitive men are those derived from splanchnic sources.

Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period.

Despite consistent evidence that abnormalities of fatty acid delivery and storage underlie the metabolic defects of insulin resistance, physiological pathways by which fat is stored in adipose tissue and skeletal muscle are not clear. We used a combination of stable isotope labeling and arteriovenous difference measurements to elucidate pathways of postprandial fat deposition in adipose tissue and skeletal muscle in healthy humans. A test meal containing [U-(13)C]palmitate was combined with intravenous infusion of [(2)H(2)]palmitate to label plasma fatty acids and VLDL-triglyceride. Both dietary (chylomicron) and VLDL-triglyceride were cleared across adipose tissue and muscle, though with greater fractional extraction of the chylomicron-triglyceride. In adipose tissue there was significant uptake of plasma nonesterified fatty acids (NEFAs) in the postprandial but not the fasting state. However, this was minor in comparison with chylomicron-triglyceride fatty acids. We modeled the fate of fatty acids released by lipoprotein lipase (LPL). There was clear preferential uptake of these fatty acids compared with plasma NEFAs. In muscle, there was unexpected evidence for release of LPL-derived fatty acids into the plasma. With this integrative physiological approach, we have revealed hidden complexities in pathways of fatty acid uptake in adipose tissue and skeletal muscle.

Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism.

BACKGROUND: Resistant starch may modulate insulin sensitivity, although the precise mechanism of this action is unknown. OBJECTIVE: We studied the effects of resistant starch on insulin sensitivity and tissue metabolism. DESIGN: We used a 4-wk supplementation period with 30 g resistant starch/d, compared with placebo, in 10 healthy subjects and assessed the results by using arteriovenous difference methods. RESULTS: When assessed by euglycemic-hyperinsulinemic clamp, insulin sensitivity was higher after resistant starch supplementation than after placebo treatment (9.7 and 8.5 x 10(-2) mg glucose x kg(-1) x min(-1) x (mU insulin/L)(-1), respectively; P = 0.03); insulin sensitivity during the meal tolerance test (MTT) was 33% higher (P = 0.05). Forearm muscle glucose clearance during the MTT was also higher after resistant starch supplementation (P = 0.03) despite lower insulin concentrations (P = 0.02); glucose clearance adjusted for insulin was 44% higher. Subcutaneous abdominal adipose tissue nonesterified fatty acid (NEFA; P = 0.02) and glycerol (P = 0.05) release were lower with resistant starch supplementation, although systemic NEFA concentrations were not significantly altered. Short-chain fatty acid concentrations (acetate and propionate) were higher during the MTT (P = 0.05 and 0.01, respectively), as was acetate uptake by adipose tissue (P = 0.03). Fasting plasma ghrelin concentrations were higher with resistant starch supplementation (2769 compared with 2062 pg/mL; P = 0.03), although postprandial suppression (40-44%) did not differ significantly. Measurements of gene expression in adipose tissue and muscle were uninformative, which suggests effects at a metabolic level. The resistant starch supplement was well tolerated. CONCLUSION: These results suggest that dietary supplementation with resistant starch has the potential to improve insulin sensitivity. Further studies in insulin-resistant persons are needed.

A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects.

CONTEXT: Low-grade inflammation in adipose tissue may contribute to insulin resistance in obesity. However, the roles of individual inflammatory mediators in adipose tissue are poorly understood. OBJECTIVES: The objective of this study was to determine which inflammation markers are most overexpressed at the gene level in adipose tissue in human obesity and how this relates to corresponding protein secretion. DESIGN: We examined gene expression profiles in 17 lean and 20 obese subjects. The secretory pattern of relevant corresponding proteins was examined in human s.c. adipose tissue or isolated fat cells in vitro and in vivo in several obese or lean cohorts. RESULTS: In ranking gene expression, defined pathways associated with obesity and immune and defense responses scored high. Among seven markedly overexpressed chemokines, only monocyte chemoattractant protein 1 (MCP1) was released from adipose tissue and isolated fat cells in vitro. In obesity, the secretion and expression of MCP1 in adipose tissue pieces were more than 6- and 2-fold increased, respectively, but there was no change in circulating MCP1 levels. There was no net release of MCP1, but there was a net release of leptin, in vivo from adipose tissue into the circulation. CONCLUSIONS: Obesity is associated with the increased expression of several chemokine genes in adipose tissue. However, only MCP1 is secreted into the extracellular space, where it primarily acts as a local factor, because little or no spillover into the circulation occurs. MCP1 influences the function of adipocytes, is a recruitment factor for macrophages, and may be a crucial link among chemokines between adipose tissue inflammation and insulin resistance.