Michael Rocco

A low–glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese prediabetic humans

BACKGROUND The optimal lifestyle intervention that reverses diabetes risk factors is not known. OBJECTIVE We examined the effect of a low-glycemic index (GI) diet and exercise intervention on glucose metabolism and insulin secretion in obese, prediabetic individuals. DESIGN Twenty-two participants [mean ± SEM age: 66 ± 1 y; body mass index (in kg/m(2)): 34.4 ± 0.8] underwent a 12-wk exercise-training intervention (1 h/d for 5 d/wk at ≈ 85% of maximum heart rate) while randomly assigned to receive either a low-GI diet (LoGIX; 40 ± 0.3 units) or a high-GI diet (HiGIX; 80 ± 0.6 units). Body composition (measured by using dual-energy X-ray absorptiometry and computed tomography), insulin sensitivity (measured with a hyperinsulinemic euglycemic clamp with [6,6-(2)H(2)]-glucose), and oral glucose-induced insulin and incretin hormone secretion were examined. RESULTS Both groups lost equal amounts of body weight (-8.8 ± 0.9%) and adiposity and showed similar improvements in peripheral tissue (+76.2 ± 14.9%) and hepatic insulin sensitivity (+27.1 ± 7.1%) (all P < 0.05). However, oral glucose-induced insulin secretion was reduced only in the LoGIX group (6.59 ± 0.86 nmol in the prestudy compared with 4.70 ± 0.67 nmol in the poststudy, P < 0.05), which was a change related to the suppressed postprandial response of glucose-dependent insulinotropic polypeptide. When corrected for changes in β cell glucose exposure, changes in insulin secretion were attenuated in the LoGIX group but became significantly elevated in the HiGIX group. CONCLUSIONS Although lifestyle-induced weight loss improves insulin resistance in prediabetic individuals, postprandial hyperinsulinemia is reduced only when a low-GI diet is consumed. In contrast, a high-GI diet impairs pancreatic β cell and intestinal K cell function despite significant weight loss. These findings highlight the important role of the gut in mediating the effects of a low-GI diet on type 2 diabetes risk reduction.

Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience.

BACKGROUND Statin therapy is a proven effective treatment of hyperlipidemia. However, a significant number of patients cannot tolerate statins. This study was conducted to review treatment strategies for patients intolerant to statin therapy with a focus on intermittent statin dosing. METHODS AND RESULTS We performed a retrospective analysis of medical records of 1,605 patients referred to the Cleveland Clinic Preventive Cardiology Section for statin intolerance between January 1995 and March 2010 with at least a 6-month follow-up. The changes in lipid profile, achievement of low-density lipoprotein cholesterol (LDL-C) goals, and statin tolerance rate were analyzed. Most (72.5%) of patients with prior statin intolerance were able to tolerate a statin for the median follow-up time of 31 months. Patients on intermittent statin dosing (n = 149) had significantly lower LDL-C reduction compared with daily dosing group (n = 1,014; 21.3% ± 4.0% vs 27.7% ± 1.4%, P < .04). However, compared with the statin discontinued group (n = 442), they had a significantly higher LDL-C reduction (21.3% ± 4.0% vs 8.3 ± 2.2%, P < .001), and a significantly higher portion achieved their Adult Treatment Panel III goal of LDL-C (61% vs 44%, P < .05). There was a trend toward a decrease in all-cause mortality at 8 years for patients on daily and intermittent statin dosing compared with those who discontinued statin (P = .08). CONCLUSIONS Most patients with previous statin intolerance can tolerate subsequent trial of statin. A strategy of intermittent statin dosing can be an effective therapeutic option in some patients and may result in reduction in LDL-C and achievement of LDL-C goals.

Improved Pancreatic β-Cell Function in Type 2 Diabetic Patients After Lifestyle-Induced Weight Loss Is Related to Glucose-Dependent Insulinotropic Polypeptide

OBJECTIVE Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in β-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis. RESEARCH DESIGN AND METHODS Twenty-nine older, obese (aged 65 ± 1 years; BMI 33.6 ± 1.0 kg/m2) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese-NGT), underwent 3 months of nutritional counseling and exercise training. β-Cell function (oral glucose–induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined. RESULTS After exercise and diet-induced weight loss (−5.0 ± 0.7 kg), oral glucose–induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P < 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 ± 0.26 vs. 2.04 ± 0.46 arbitrary units; P < 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group. CONCLUSIONS After lifestyle-induced weight loss, improvements in oral glucose–induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated β-cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells.

A Low-Glycemic Index Diet and Exercise Intervention Reduces TNFα in Isolated Mononuclear Cells of Older, Obese Adults

Low-glycemic index diets and exercise independently improve glucose tolerance and reduce diabetes risk. However, the combined effect of a low-glycemic index diet and exercise on inflammation and glucose metabolism is not known. Therefore, we randomized 28 insulin-resistant adults (age: 66 ± 1 y; BMI: 34.2 ± 0.7 kg · m(-2)) to a 12-wk, low (LGI = 40) or high- (HGI = 80) glycemic index diet plus aerobic exercise (5 d · wk(-1), 60 min · d(-1), 80-85% heart rate(max)) intervention. All food and fluids were provided during the study. Inflammation was assessed from cytokine (TNFα and IL-6) secretion using peripheral blood mononuclear cells (MNC) stimulated overnight with LPS. Glycemic response was determined following ingestion of a 75-g glucose solution. Fasting blood samples were collected for additional cytokine [TNFα, IL-6, and monocyte chemoattractant protein 1 (MCP-1)] analysis. Both interventions decreased BMI (P < 0.001), fasting plasma glucose (P = 0.01), and insulin (P = 0.02). The glycemic response was reduced only in the LGI group (P = 0.04). Plasma and MNC-derived TNFα secretion were reduced in the LGI group (P = 0.02) but increased in the HGI group (P = 0.02). Secretion of IL-6 from MNC and plasma IL-6 and MCP-1 concentrations were reduced in the LGI group. The change in MNC-derived TNFα (r = 0.43; P = 0.04) and plasma MCP-1 (r = 0.44; P = 0.04) correlated with decreases in the glycemic response. These data highlight the importance of diet composition in the treatment and prevention of inflammation and hyperglycemia. A low-glycemic index diet has antiinflammatory and antidiabetogenic effects when combined with exercise in older, obese prediabetics.

Randomized trial on the effects of a 7-d low-glycemic diet and exercise intervention on insulin resistance in older obese humans

BACKGROUND The optimal combination of diet and exercise that produces the greatest reversal of obesity-related insulin resistance is unknown. OBJECTIVES We examined the effects of a combined 7-d low-glycemic index (low-GI) diet and exercise training intervention on insulin sensitivity in older obese humans. DESIGN Participants [n = 32; mean (+/-SEM) age: 66 +/- 1 y; body mass index (in kg/m(2)): 33.8 +/- 0.7] were randomly assigned to a parallel, double-blind, controlled-feeding trial and underwent supervised aerobic exercise (EX; 60 min/d at 80-85% maximum heart rate) in combination with either a low-GI (LoGI + EX: 41.1 +/- 0.4) or a high-GI (HiGI + EX: 80.9 +/- 0.6) diet. All meals were provided and were isocaloric to individual energy requirements. Insulin sensitivity and hepatic glucose production were assessed with a 40-mU x m(-2) x min(-1) hyperinsulinemic euglycemic clamp combined with a [6,6-(2)H(2)]-glucose infusion. RESULTS After the intervention, small decreases were observed in body weight (-1.6 +/- 0.2 kg; P < 0.0001) and fat mass (-1.7 +/- 0.9%; P = 0.004) in both groups. Maximal aerobic capacity ( O(2)max) also improved slightly (0.06 +/- 0.02 L/min; P = 0.004). Resting systolic blood pressure, fasting glucose, insulin, triglycerides, and cholesterol all decreased after the study (all P < 0.05). Larger changes in systolic blood pressure and O(2max) were seen in the LoGI + EX group. Insulin-stimulated glucose disposal (P < 0.001), insulin suppression of hepatic glucose production (P = 0.004), and postabsorptive fat oxidation (P = 0.03) improved equally in both groups after the intervention. CONCLUSIONS These findings suggest that the metabolic improvements after short-term exercise training in older obese individuals are dependent on increased physical activity and are not influenced by a low-GI diet. However, a low-GI diet has added benefit in alleviating hypertension, thus reducing the risk of diabetic and vascular complications.

Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults.

Background: The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low (LoGIx)- or high (HiGIx)-glycemic index diet on the severity of the metabolic syndrome (Z-score). Methods: Twenty-one adults (66.2 ± 1.1 years; BMI = 35.3 ± 0.9 kg/m2) with the metabolic syndrome were randomized to 12 weeks of exercise (60 min/day for 5 days/week at about 85% HRmax) and provided a LoGIx (n = 11) or HiGIx (n = 10) diet. Z-scores were determined from: blood pressure, triglycerides (TGs), high-density lipoproteins (HDLs), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and nonesterfied fatty acid (NEFA) suppression were also assessed. Results: LoGIx and HiGIx diets decreased body mass and insulin resistance and increased aerobic fitness comparably (p < 0.05). LoGIx and HiGIx diets decreased the Z-score similarly as each intervention decreased blood pressure, TGs, FPG and WC (p < 0.05). The HiGIx diet tended to suppress NEFA during insulin stimulation compared with the LoGIx diet (p = 0.06). Conclusions: Our findings highlight that exercise with weight loss reduces the severity of the metabolic syndrome whether individuals were randomized to a HiGIx or a LoGIx diet.

Design and Rationale of the GAUSS‐2 Study Trial: A Double‐Blind, Ezetimibe‐Controlled Phase 3 Study of the Efficacy and Tolerability of Evolocumab (AMG 145) in Subjects With Hypercholesterolemia Who Are Intolerant of Statin Therapy

Statins effectively lower low‐density lipoprotein cholesterol (LDL‐C), reducing cardiovascular morbidity and mortality. Most patients tolerate statins well, but approximately 10% to 20% experience side effects (primarily muscle‐related) contributing to diminished compliance or discontinuation of statin therapy and subsequent increase in cardiovascular risk. Statin‐intolerant patients require more effective therapies for lowering LDL‐C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a compelling target for LDL‐C–lowering therapy. Evolocumab (AMG 145) is a fully human monoclonal antibody that binds PCSK9, inhibiting its interaction with the LDL receptor to preserve LDL‐receptor recycling and reduce LDL‐C. Phase 2 studies have demonstrated the safety, tolerability, and preliminary efficacy of subcutaneous evolocumab in diverse populations, including statin‐intolerant patients. This article describes the rationale and design of the Goal Achievement After Utilizing an anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 2 (GAUSS‐2) trial, a randomized, double‐blind, ezetimibe‐controlled, multicenter phase 3 study to evaluate the effects of 12 weeks of evolocumab 140 mg every 2 weeks or 420 mg every month in statin‐intolerant patients with hypercholesterolemia. Eligible subjects were unable to tolerate effective doses of ≥2 statins because of myalgia, myopathy, myositis, or rhabdomyolysis that resolved with statin discontinuation. The primary objective of the study is to assess the effects of evolocumab on percentage change from baseline in LDL‐C. Secondary objectives include evaluation of safety and tolerability, comparison of the effects of evolocumab vs ezetimibe on absolute change from baseline in LDL‐C, and percentage changes from baseline in other lipids. Recruitment of approximately 300 subjects was completed in August 2013.

β-Cell dysfunction is associated with metabolic syndrome severity in adults.

BACKGROUND Metabolic syndrome is prevalent in adults characterized by increased visceral adiposity and insulin resistance (IR). However, the link between pancreatic β-cell function and metabolic syndrome severity in adults across the glucose spectrum is unknown. We hypothesized that poor β-cell function would independently predict a higher metabolic syndrome Z-score (i.e., severity). METHODS Seventy (12 normal glucose tolerant, 37 prediabetic, 21 type 2 diabetic) obese adults [62.4±1.1 year; 34.6±0.6 kg/m(2); data are mean±standard error of the mean (SEM)] participated in this cross-sectional study. A 2-hr 75-gram oral glucose tolerance test (OGTT) was administered, and insulin and glucose area under the curve was determined for calculations of insulin action. Fasting and glucose-stimulated insulin secretion was calculated using homeostasis model assessment of insulin secretion (HOMA-B) and the insulinogenic index (i.e., I(0-30)/Glc(0-30) or I(60-120)/Glc(60-120)), respectively. Fasting and postprandial insulin sensitivity was assessed by HOMA-IR and the Matsuda Index, respectively. β-cell function was estimated using the disposition index via HOMA-B/HOMA-IR, I(0-30)/Glc(0-30) or I(60-120)/Glc(60-120) × Matsuda Index, which represents basal, first-, and second-phase insulin release, respectively. Body composition (via computerized tomography and dual X-ray absorptiometry) and sex-specific metabolic syndrome Z-scores were calculated from waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoproteins. RESULTS Compared to those with normal glucose tolerance, visceral fat and IR were higher and β-cell function was lower in adults with glucose intolerance and type 2 diabetes mellitus. Elevated visceral fat and IR (HOMA-IR and Matsuda Index) correlated with elevated Z-scores (r=0.51, r=0.54, r=-0.49; all P<0.002, respectively). Basal, first-, and second-phase β-cell function correlated with low Z-scores (r=-0.59, r=-0.51, and r=-0.43, all P<0.001). Insulin secretion significantly predicted the Z-score independent of sex, body fat, blood lipids, blood pressure, IR, and glucose metabolism (P<0.005). CONCLUSION β-cell dysfunction is highly correlated with the severity of metabolic syndrome in adults. Future work is warranted to elucidate the mechanism by which cardiometabolic disturbances influence insulin secretion.

New cholesterol guidelines: worth the wait?

An appraisal of the controversial new guidelines, with case scenarios illustrating their advantages and shortcomings.

A Community-Based Exercise and Support Group Program in African-American Breast Cancer Survivors (ABCs).

African-American (AA) women have higher rates of breast cancer (BCa) mortality than Caucasian women, and a recent study using data from the Surveillance, Epidemiology and End Results (SEER) registry suggests that this disparity may be due, in part, to the poorer health status of AAs at diagnosis and not treatment related issues. Randomized controlled trials involving supervised aerobic and resistance exercise have shown improved body composition and improvement in cancer-related biomarkers in BCa patients and may lead to improved recurrence and survival rates; however, most trials have focused on Caucasians and many have been conducted in academic- and clinic-based settings. We evaluated the feasibility of conducting a 20-week, supervised, resistance training, group exercise intervention coupled with a support group and home walking program utilizing facilities and personnel at a community cancer support center (The Gathering Place, Beachwood, Ohio) in AA Stage I-III BCa survivors who were within 12 months of completing treatment (surgery, chemotherapy, and/or breast irradiation); and, evaluated the potential effects of this intervention on physical measures and cancer-related biomarkers. 27 patients provided informed consent and 19 participated in the program. On average, attendance rates were 70.0% ± 19.1% for the exercise sessions and 63.1% ± 13.8% for the support group. We observed a significant decrease in circulating C-peptide levels (B: 893.9 ± 399.1 pg/mL; EOI: 723.9 ± 319.0 pg/mL; p=0.01). Although we did not observe a significant decrease in weight in the entire sample, there was a significant decrease in waist circumference and percent total body fat among those who attended 70% or more of the exercise sessions. In summary, we demonstrated that conducting lifestyle interventions in AA BCa survivors in a community setting is feasible. Future interventions should invoke strategies to enhance adherence and include a structured dietary intervention to enable greater weight loss.