Insulin Sensitivity In Nondiabetic Subjects Research Articles

Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials

Background: High fructose consumption has been suggested to contribute to several features of metabolic syndrome including insulin resistance, but to our knowledge, no previous meta-analyses have investigated the effect of fructose on insulin sensitivity in nondiabetic subjects.Objective: We performed a systematic review and meta-analysis of controlled diet-intervention studies in nondiabetic subjects to determine the effect of fructose on insulin sensitivity.Design: We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials on the basis of predetermined eligibility criteria. Two investigators independently performed the study selection, quality assessment, and data extraction. Results were pooled with the use of the generic inverse-variance method with random effects weighting and were expressed as mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs.Results: Twenty-nine articles that described 46 comparisons in 1005 normal-weight and overweight or obese participants met the eligibility criteria. An energy-matched (isocaloric) exchange of dietary carbohydrates by fructose promoted hepatic insulin resistance (SMD: 0.47; 95% CI: 0.03, 0.91; P = 0.04) but had no effect on fasting plasma insulin concentrations (MD: −0.79 pmol/L; 95% CI: −6.41, 4.84 pmol/L; P = 0.78), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD: 0.13; 95% CI: −0.07, 0.34; P = 0.21), or glucose disposal rates under euglycemic hyperinsulinemic clamp conditions (SMD: 0.00; 95% CI: 20.41, 0.41; P = 1.00). Hypercaloric fructose (∼25% excess of energy compared with that of the weight-maintenance control diet) raised fasting plasma insulin concentrations (MD: 3.38 pmol/L; 95% CI: 0.03, 6.73 pmol/L; P < 0.05) and induced hepatic insulin resistance (SMD: 0.77; 95% CI: 0.28, 1.26; P < 0.01) without affecting the HOMA-IR (MD: 0.18; 95% CI: −0.02, 0.39; P = 0.08) or glucose disposal rates (SMD: 0.10; 95% CI: −0.21, 0.40; P = 0.54). Results may have been limited by the low quality, small sample size, and short duration (mostly <60 d) of included trials.Conclusions: Short-term fructose consumption, in isocaloric exchange or in hypercaloric supplementation, promotes the development of hepatic insulin resistance in nondiabetic adults without affecting peripheral or muscle insulin sensitivity. Larger and longer-term studies are needed to assess whether real-world fructose consumption has adverse effects on insulin sensitivity and long-term outcomes.

Increased serum levels of advanced glycation end-products is associated with severity of sleep disordered breathing but not insulin sensitivity in non-diabetic men with obstructive sleep apnoea

Patients with diabetes mellitus are known to have increased serum levels of advanced glycation end-products (AGEs), and this is also associated with insulin resistance. This study aimed to investigate the relationship between serum AGEs and insulin sensitivity in non-diabetic subjects with obstructive sleep apnoea (OSA). Adult males with no known comorbidities were recruited from the sleep clinic of a university teaching hospital. They underwent overnight in-laboratory polysomnography. Fasting blood was taken to measure serum AGE and plasma glucose levels. Insulin sensitivity was estimated using the short insulin tolerance test. In total, 105 subjects with a mean age of 43.5 (standard deviation [SD] 9.2)years, mean body mass index of 27.1 (SD 4.0)kg/m(2), and median apnoea-hypopnoea index (AHI) of 17 (interquartile range 5-46) were analysed. Serum AGE levels were significantly higher in subjects with OSA (AHI ≥5), compared with those without OSA (AHI <5) (3.9 [SD 1.2] vs. 3.2 [SD 0.8]μg/ml, respectively; P=0.037) after adjusting for confounders. AGE levels were positively correlated with AHI (r=0.318, P=0.001), but not with insulin sensitivity. AGE levels decreased in subjects with moderate-to-severe OSA who received continuous positive airway pressure (CPAP) treatment for three months (n=18, P=0.017). Serum AGE levels correlate with AHI in non-diabetic adult males. This relationship cannot be explained by insulin sensitivity. Supporting the hypothesis of a direct relationship between AHI and AGEs, AGE levels were found to decline with CPAP therapy.

Treatment with Anakinra Improves Disposition Index But Not Insulin Sensitivity in Nondiabetic Subjects with the Metabolic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study

Obesity induces low-grade inflammation that may promote the development of insulin resistance. IL-1 is one of the key inflammatory factors. The objective of the study was to demonstrate improvement of insulin sensitivity by blocking IL-1. This was a randomized, double-blind, crossover study. The study was based on ambulatory care. Participants included nondiabetic, obese subjects with the metabolic syndrome. Intervention included 150 mg anakinra sc once daily or matching placebo for 4 wk. Insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. A total of 13 of 19 subjects completed the study. Although anakinra treatment resulted in a significantly lower level of inflammation illustrated by a reduction in circulating C-reactive protein concentrations and leukocyte numbers, insulin sensitivity was not significantly different after anakinra treatment (2.8 × 10(-2) ± 0.5 × 10(-2)) compared with placebo treatment (2.4 × 10(-2) ± 0.3 × 10(-2) μmol/kg(-1) · min(-1) · pmol(-1), P = 0.15). Adipose tissue examination, performed to analyze local effects of IL-1 receptor antagonist, showed an increased influx of macrophages after treatment with anakinra most likely due to an injection site reaction caused by the vehicle (0.28 ± 0.05 vs. 0.11 ± 0.01 macrophages per adipocyte, P = 0.005). The differences in individual subject insulin sensitivity after anakinra as compared with placebo between subjects were negatively correlated with macrophage infiltration into the adipose tissue (r(2) = 0.46, P = 0.01). The disposition index increased significantly after anakinra treatment (P = 0.04), reflecting an improvement in β-cell function. Our results suggest that anakinra does not improve insulin sensitivity in obese, insulin-resistant, nondiabetic subjects.

The Pro12Ala polymorphism of the PPAR γ2 gene is associated with hepatic glucose uptake during hyperinsulinemia in subjects with type 2 diabetes mellitus

The Ala12 allele of the peroxisome proliferator–activated receptor γ gene ( PPARG2) has been associated with reduced risk of type 2 diabetes mellitus (T2DM) and increased whole-body and skeletal muscle insulin sensitivity in nondiabetic subjects. The effect of the Pro12Ala polymorphism on tissue specific insulin sensitivity in subjects with T2DM has not been previously investigated. We studied the effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake (GU) in T2DM subjects, and the rates of hepatic GU in nondiabetic and T2DM subjects during hyperinsulinemia. Our study included 105 T2DM subjects whose whole-body, skeletal muscle, subcutaneous adipose tissue, and hepatic GUs were measured using 18F-fluorodeoxyglucose and positron emission tomography during the hyperinsulinemic euglycemic clamp. Hepatic GU was also measured in 68 nondiabetic subjects. In obese (body mass index ≥27 kg/m 2) subjects with T2DM, the rate of hepatic GU was 28% lower in subjects with the Pro12Pro genotype than in carriers of the Ala12 allele ( P = .001); and a similar trend was observed in nondiabetic obese subjects ( P = .137). No effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, or subcutaneous adipose tissue GU was observed in T2DM subjects. We conclude that the Ala12 allele of PPARG2 is associated with higher hepatic GU in obese subjects with T2DM.

Muscle and Liver Insulin Resistance Indexes Derived From the Oral Glucose Tolerance Test

To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18-70 years, BMI 20-65 kg/m(2)) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose(0-30)[AUC] x insulin(0-30)[AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin x basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt / I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.

Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia

By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic-hyperinsulinaemic clamp after 12 weeks of both treatment periods. Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides -28%; LDL-c -50%; VLDL-c -56%, VLDL-TG -39%) and both parameters of low-grade inflammation (as measured by hsCRP, -16%) and oxidative stress (as measured by plasma-oxLDL, -55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41.7 +/- 17.4 vs. 40.6 +/- 11.1 L kg(-1) min(-1), placebo vs. rosuvastatin, P = 0.71). Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.

Oral Magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial

Although hypomagnesemia reduces insulin sensitivity, benefits of magnesium supplementation to non-diabetic insulin resistant subjects has not been established. Our purpose was to determine whether oral magnesium supplementation with magnesium chloride (MgCl2) 2.5 g daily modify insulin sensitivity in non-diabetic subjects. This study was a 3 months randomized double-blind placebo-controlled trial. Apparently healthy subjects were eligible to participate if they had insulin resistance (HOMA-IR index equal or greater than 3.0) and hypomagnesemia (Serum magnesium levels equal or lower than 0.74 mmol/l). Subjects were randomized to receive either, MgCl2 2.5 g daily or placebo by 3-months. At baseline there were not significant anthropometric or laboratory differences between both groups. At ending of the study, magnesium-supplemented subjects significantly increased their serum magnesium levels (0.61 +/- 0.08 to 0.81 +/- 0.08 mmol/l, p<0.0001) and reduced HOMA-IR index (4.6 +/- 2.8 to 2.6 +/- 1.1, p<0.0001), whereas control subjects did not (0.62 +/- 0.08 to 0.61 +/- 0.08 mmol/l, p=0.063 and 5.2 +/- 1.9 to 5.3 +/- 2.9, p=0.087). Oral magnesium supplementation improves insulin sensitivity in hypomagnesemic non-diabetic subjects. Clinical implications of this finding have to be established.

Comparison of the Effects on Insulin Sensitivity of High Carbohydrate and High Fat Diets in Normal Subjects*

To examine whether achievable dietary changes influence insulin sensitivity, we performed euglycemic hyperinsulinemic glucose clamps in eight normal subjects who were prescribed high carbohydrate and high fat diets. The high carbohydrate diet was more than 50% (of energy intake) carbohydrate and less than 30% fat; the high fat diet was more than 45% fat (predominantly saturated) and less than 40% carbohydrate. The diets were consumed over consecutive 3-week periods in random sequence. The mean whole body glucose uptake during the glucose clamps was similar after the high carbohydrate (48.3 mumol/kg.min) and high fat diets (47.0 mumol/kg.min; P = 0.5; 95% confidence interval for the difference, -3.4 to 5.9 mumol/kg.min). Fasting blood glucose and serum insulin concentrations were also unchanged. In contrast, there were substantial effects on lipoprotein metabolism. During the high carbohydrate diet, fasting serum cholesterol decreased by 17% (P = 0.06), low density lipoprotein cholesterol decreased by 20% (P = 0.05), high density lipoprotein cholesterol decreased by 24% (P less than 0.005), and triglyceride increased by 33% (P = 0.06) compared with levels during the high fat diet. These results suggest that practically achievable high carbohydrate diets do not enhance insulin sensitivity in nondiabetic subjects and have net effects on lipoprotein metabolism that may be unfavorable.