High-intensity interval training combining rowing and cycling improves but does not restore beta-cell function in type 2 diabetes.

Aim: We investigated whether a high-intensity interval training (HIIT) protocol could restore beta-cell function in type 2 diabetes compared with sedentary obese and lean individuals. Materials and methods: In patients with type 2 diabetes, and age-matched, glucose-tolerant obese and lean controls, we examined the effect of 8 weeks of supervised HIIT combining rowing and cycling on the acute (first-phase) and second-phase insulin responses, beta-cell function adjusted for insulin sensitivity (disposition index), and serum free fatty acid (FFA) levels using the Botnia clamp (1-h IVGTT followed by 3-h hyperinsulinemic-euglycemic clamp). Results: At baseline, patients with type 2 diabetes had reduced insulin sensitivity (~40%), acute insulin secretion (~13-fold), and disposition index (>35-fold), whereas insulin-suppressed serum FFA was higher (⁓2.5-fold) compared with controls (all P < 0.05). The HIIT protocol increased insulin sensitivity in all groups (all P < 0.01). In patients with type 2 diabetes, this was accompanied by a large (>200%) but variable improvement in the disposition index (P < 0.05). Whereas insulin sensitivity improved to the degree seen in controls at baseline, the disposition index remained markedly lower in patients with type 2 diabetes after HIIT (all P < 0.001). In controls, HIIT increased the disposition index by ~20-30% (all P < 0.05). In all groups, the second-phase insulin responses and insulin-suppressed FFA levels were reduced in response to HIIT (all P < 0.05). No group differences were seen in these HIIT-induced responses. Conclusion: HIIT combining rowing and cycling induced a large but variable increase in beta-cell function adjusted for insulin sensitivity in type 2 diabetes, but the disposition index remained severely impaired compared to controls, suggesting that this defect is less reversible in response to exercise training than insulin resistance. Trial registration: ClinicalTrials.gov (NCT03500016).

Muscle Lipid Oxidation Is Not Affected by Obstructive Sleep Apnea in Diabetes and Healthy Subjects.

The molecular mechanisms linking obstructive sleep apnea (OSA) with type 2 diabetes mellitus (T2DM) remain unclear. This study investigated the effect of OSA on skeletal muscle lipid oxidation in nondiabetic controls and in type 2 diabetes (T2DM) patients. Forty-four participants matched for age and adiposity were enrolled: nondiabetic controls (control, n = 14), nondiabetic patients with severe OSA (OSA, n = 9), T2DM patients with no OSA (T2DM, n = 10), and T2DM patients with severe OSA (T2DM + OSA, n = 11). A skeletal muscle biopsy was performed; gene and protein expressions were determined and lipid oxidation was analyzed. An intravenous glucose tolerance test was performed to investigate glucose homeostasis. No differences in lipid oxidation (178.2 ± 57.1, 161.7 ± 22.4, 169.3 ± 50.9, and 140.0 ± 24.1 pmol/min/mg for control, OSA, T2DM, and T2DM+OSA, respectively; p > 0.05) or gene and protein expressions were observed between the groups. The disposition index, acute insulin response to glucose, insulin resistance, plasma insulin, glucose, and HBA1C progressively worsened in the following order: control, OSA, T2DM, and T2DM + OSA (p for trend <0.05). No association was observed between the muscle lipid oxidation and the glucose metabolism variables. We conclude that severe OSA is not associated with reduced muscle lipid oxidation and that metabolic derangements in OSA are not mediated through impaired muscle lipid oxidation.

Glucose Metabolism and Metabolomic Changes in Response to Prolonged Fasting in Individuals with Obesity, Type 2 Diabetes and Non-Obese People-A Cohort Trial.

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.

Overexpressed beta cell CART increases insulin secretion in mouse models of insulin resistance and diabetes.

Impaired beta cell function and beta cell death are key features of type 2 diabetes (T2D). Cocaine- and amphetamine-regulated transcript (CART) is necessary for normal islet function in mice. CART increases glucose-stimulated insulin secretion in vivo in mice and in vitro in human islets and CART protects beta cells against glucotoxicity-induced cell death in vitro in rats. Furthermore, beta cell CART is upregulated in T2D patients and in diabetic rodent models as a consequence of hyperglycaemia. The aim of this study was to assess the impact of upregulated beta cell CART on islet hormone secretion and glucose homeostasis in a transgenic mouse model. To this end, mice with beta cell-specific overexpression of CART (CARTtg mice) were generated. CARTtg mice challenged by aging, high fat diet feeding or streptozotocin treatment were phenotyped with respect to in vivo and in vitro insulin and glucagon secretion, glucose homeostasis, and beta cell mass. In addition, the impact of adenoviral overexpression of CART on insulin secretion was studied in INS-1 832/13 cells. CARTtg mice had a normal metabolic phenotype under basal conditions. On the other hand, with age CARTtg mice displayed increased insulin secretion and improved glucose elimination, compared with age-matched WT mice. Furthermore, compared with WT controls, CARTtg mice had increased insulin secretion after feeding a high fat diet, as well as lower glucose levels and higher insulin secretion after streptozotocin treatment. Viral overexpression of CART in INS-1 832/13 cells resulted in increased glucose-stimulated insulin secretion. Together, these results imply that beta cell CART acts to increase insulin secretion when beta cell function is challenged. We propose that the increase in beta cell CART is part of a compensatory mechanisms trying to counteract the hyperglycaemia in T2D.

The Impact of Exogenous Insulin Input on Calculating Hepatic Clearance Parameters.

OBJECTIVE: Model-based metabolic tests require accurate identification of subject-specific parameters from measured assays. Insulin assays are used to identify insulin kinetics parameters, such as general and first-pass hepatic clearances. This study assesses the impact of intravenous insulin boluses on parameter identification precision. METHOD: Insulin and C-peptide data from two intravenous glucose tolerance test (IVGTT) trials of healthy adults (N = 10 × 2; denoted A and B), with (A) and without (B) insulin modification, were used to identify insulin kinetics parameters using a grid search. Monte Carlo analysis (N = 1000) quantifies variation in simulation error for insulin assay errors of 5%. A region of parameter values around the optimum was identified whose errors are within variation due to assay error. A smaller optimal region indicates more precise practical identifiability. Trial results were compared to assess identifiability and precision. RESULTS: Trial B, without insulin modification, has optimal parameter regions 4.7 times larger on average than Trial A, with 1-U insulin bolus modification. Ranges of optimal parameter values between trials A and B increase from 0.04 to 0.12 min-1 for hepatic clearance and from 0.07 to 0.14 for first-pass clearance on average. Trial B's optimal values frequently lie outside physiological ranges, further indicating lack of distinct identifiability. CONCLUSIONS: A small 1-U insulin bolus improves identification of hepatic clearance parameters by providing a smaller region of optimal parameter values. Adding an insulin bolus in metabolic tests can significantly improve identifiability and outcome test precision. Assay errors necessitate insulin modification in clinical tests to ensure identifiability and precision.

Impaired glucose tolerance and indeterminate glycemia in cystic fibrosis.

Oral glucose tolerance testing (OGTT) is the primary method to screen for and diagnose cystic fibrosis-related diabetes (CFRD). Diagnostic thresholds as currently defined are based on microvascular complications seen in type 2 diabetes. Abnormal glucose tolerance (AGT) refers to OGTT glucose elevations outside the normal range and encompasses both impaired and indeterminate glucose tolerance. Current guidelines define impaired glucose tolerance (IGT) as a 2-hour glucose of 140-199 mg/dL (7.8-11 mmol/L) and indeterminate glucose tolerance (INDET) as any mid-OGTT glucose ≥ 200 mg/dL (11.1 mmol/L) with a normal fasting and 2 h glucose. There is growing evidence that AGT also has associations with CF-centered outcomes including pulmonary decline, hospitalizations, and weight loss. Here we aim to review the historical emergence of glucose tolerance testing, review relevance to risk stratification for CFRD, discuss alternate cutoffs for identifying AGT earlier, and highlight the need for larger, future studies to inform our understanding of the implications of IGT and INDET on CF health.

Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors.

The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FEL-P1, CLP-P1; FEL-P2, CLP-P2) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CLT-P1 and CLT-P2. A statistically significant difference between DIRKO and WT was found in CLT-P1 (0.61 [0.48-0.82] vs. 0.51 [0.46-0.65] (median [interquartile range]); p = 0.02), which was reflected in the peripheral component, CLP-P1 (0.18 [0.13-0.27] vs. 0.15 [0.11-0.22]; p = 0.04), but not in the hepatic component, FEL-P1 (29.7 [26.7-34.9] vs. 28.9 [25.7-32.0]; p = 0.18). No difference was detected between DIRKO and WT in CLT-P2 (1.38 [1.13-1.75] vs. 1.69 [1.48-1.87]; p = 0.10), neither in CLP-P2 (0.72 [0.64-0.81] vs. 0.79 [0.69-0.87]; p = 0.27) nor in FEL-P2 (37.8 [35.1-43.1] vs. 39.8 [35.8-44.2]; p = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component.

Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities.

A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

Subcutaneous transplantation of engineered islet/adipose-derived mesenchymal stem cell sheets in diabetic pigs with total pancreatectomy.

INTRODUCTION: Intraportal islet transplantation is a promising therapeutic approach for patients with type 1 diabetes mellitus (T1DM). However, despite being minimally invasive, the method has some limitations, such as short-term graft loss, portal venous thrombosis, and difficulty in collecting adequate amounts of islets. Subcutaneous islet transplantation on adipose-derived mesenchymal stem cell (ADSC) sheets has been suggested to overcome these limitations, and in this study, we have examined its feasibility in T1DM pigs. METHODS: Inguinal subcutaneous fat was harvested from young pigs and then isolated and cultured adequate ADSCs to prepare sheets. Islets were isolated from the pancreases of mature pigs and seeded on the ADSC sheets. T1DM pigs were generated by total pancreatectomy, and ADSC sheets with transplanted islets were administered subcutaneously to the waist (n = 2). The effects of the islets on the ADSC sheets and on blood glucose levels were evaluated. Insulin secretion was measured by insulin stimulation index. RESULTS: Islet viability was higher on ADSCs compared to islets alone (91.8 ± 4.3 vs. 81.7 ± 4.1%). The insulin stimulation index revealed higher glucose sensitivity of islets on ADSC sheets compared to islets alone (2.8 ± 2.0 vs. 0.8 ± 0.3). After transplantation, the blood glucose levels of two pigs were within the normal range, and sensitive insulin secretion was confirmed by intravenous glucose tolerance tests. After graftectomy, decreased insulin secretion and hyperglycemia were observed. CONCLUSIONS: Subcutaneous islet transplantation using ADSC sheets can regulate the blood glucose levels of T1DM pigs.

Intravenous Administration of Butaphosphan and Cyanocobalamin Combination to Late-Pregnant Dairy Cows Reduces Their Insulin Resistance After Calving.

Dairy cows suffer insulin resistance following parturition and lactogenesis. Several researchers attempted to reduce insulin resistance via dietary and parenteral supplementations of different substances to promote metabolic performance of dairy cows. Due to mechanisms of actions of butaphosphan in combination with cyanocobalamin, we hypothesized that this compound may reduce insulin resistance of dairy cows following parturition; hence, the effects of the intravenous administration of butaphosphan and cyanocobalamin to prepartum dairy cows on their insulin resistance after calving were evaluated. Twenty-four multiparous Holstein dairy cows were enrolled 3 weeks prior to parturition and divided into four equal groups, including control (Ctrl) and butaphosphan and cyanocobalamin (B+C) 1, 2, and 3. Ctrl cows received 15 mL of 0.9% NaCl solution and B+C 1, 2, and 3 groups intravenously received 2, 4, and 6 mL/100 kg BW of 10% butaphosphan and 0.005% cyanocobalamin combination over three periods of 3 consecutive days, including 21-19, 12-10, and 3-1 days before calving, respectively. Intravenous glucose tolerance test was performed weekly 1, 2, and 3 weeks after parturition to evaluate the insulin resistance phenomenon. Circulating levels of glucose, insulin, non-esterified fatty acids (NEFA), and beta-hydroxybutyric acid (BHBA) were assessed 1, 2, and 3 weeks after calving. Ctrl cows were the most insulin-resistant group, and B+C1 group was the most insulin-sensitive, followed by B+C2 and B+C3 groups. The NEFA and BHBA levels in the B+C3 group were significantly lower than those in the other groups. In conclusion, intravenous administration of butaphosphan and cyanocobalamin to the late-pregnant dairy cows may reduce their insulin resistance after calving.

SGLT2-i improves markers of islet endothelial cell function in db/db diabetic mice.

Islet endothelial cells produce paracrine factors important for islet beta-cell function and survival. Under conditions of type 2 diabetes, islet endothelial cells exhibit a dysfunctional phenotype including increased expression of genes involved in cellular adhesion and inflammation. We sought to determine whether treatment of hyperglycemia with the sodium glucose co-transporter 2 inhibitor empagliflozin, either alone or in combination with metformin, would improve markers of endothelial cell function in islets, assessed ex vivo, and if such an improvement is associated with improved insulin secretion in a mouse model of diabetes in vivo. For these studies, db/db diabetic mice and non-diabetic littermate controls were treated for 6 weeks with empagliflozin or metformin, either alone or in combination. For each treatment group, expression of genes indicative of islet endothelial dysfunction was quantified. Islet endothelial and beta-cell area was assessed by morphometry of immunochemically stained pancreas sections. Measurements of plasma glucose and insulin secretion during an intravenous glucose tolerance test were performed on vehicle and drug treated diabetic animals. We found that expression of endothelial dysfunction marker genes is markedly increased in diabetic mice. Treatment with either empagliflozin or metformin lowered expression of the dysfunction marker genes ex vivo, which correlated with improved glycemic control, and increased insulin release in vivo. Empagliflozin treatment was more effective than metformin alone, with a combination of the two drugs demonstrating the greatest effects. Improving islet endothelial function through strategies such as empagliflozin/metformin treatment may provide an effective approach for improving insulin release in human type 2 diabetes.

Short communication: Effect of glucose infusion dose and stage of lactation on glucose tolerance test kinetics in lactating dairy cows.

The objective for this study was to determine the effect of glucose dose and days following peak milk yield on plasma glucose, serum insulin, and plasma nonesterified fatty acids (NEFA) kinetics during an intravenous glucose tolerance test (IVGTT) in lactating dairy cattle. Six lactating Holstein dairy cows (3 primiparous and 3 multiparous) were assigned to 2 squares and received 0.092, 0.15, or 0.3 g of glucose/kg of body weight (BW) during an IVGTT at 74 and 221 d in milk (DIM), representing early (post-peak) lactation and mid lactation, respectively. Treatments were applied in a replicated Latin square design using contiguous 7-d periods within each stage of lactation. Milk production and dry matter intake were determined daily during the first 6 d of each period. The IVGTT was performed on d 7. For the IVGTT, cows were prepared with indwelling catheters in each jugular vein, and blood samples were collected at -15, -10, 5, 10, 15, 20, 30, 45, 60, 90, and 120 min relative to the glucose infusion. Samples were analyzed for plasma glucose, serum insulin, and plasma NEFA concentrations. Increasing the glucose dose during the IVGTT increased plasma glucose area under the curve (AUC), decreased glucose half-life, and increased maximal plasma glucose concentrations in plasma during the IVGTT. Greater glucose dose during the IVGTT elevated serum insulin AUC and increased nadir NEFA concentrations. Maximal plasma glucose concentration during the IVGTT was lower, whereas maximum NEFA concentration, NEFA AUC, and NEFA clearance rate were greater at 74 than at 221 DIM. Only glucose half-life was responsive to stage of lactation × glucose dose effects during the IVGTT, and the decrease in glucose half-life with increasing glucose dose was greater at 74 than at 221 DIM. Glucose AUC was greater and NEFA AUC lower for cows at 74 than at 221 DIM. For the doses tested, a glucose dose greater than 0.092 g/kg of BW resulted in peak blood glucose concentration that exceeded the previously reported renal glucose excretion threshold of 8.3 mM. There is a need for accompanying data to determine if this is the case for the glucose doses evaluated in this experiment. Based on maximal peak glucose concentrations and effects on glucose half-life, we identify 0.092 g of glucose/kg of BW (0.46 g/kg of metabolic body weight) as the preferred dose for the IVGTT for cows at 74 and 221 DIM in this study.

Analysis of a stochastic IVGTT glucose-insulin model with time delay.

Diabetes mellituse has been one of the major diseases in the world due to the high percentage of diabetics in the global population and the increasing growth rate of its onset. Identifying individual physiological characteristics, e.g., insulin sensitivity and glucose effectiveness and others, is extremely important in developing effective drugs and investigating genetic pathways causing the defects in these physiological responses. Intravenous glucose tolerance test (IVGTT) is such a protocol to determine an individual insulin sensitivity and glucose effectiveness indices. In this paper, we propose a stochastic delay differential equation model for the IVGTT protocol attempting to develop a method to increase the accuracy of parameter estimation. We first study the existence and uniqueness of the global positive solution and its asymptotic behavior of the stochastic path close to the steady state of the corresponding deterministic model. Then we develop a maximum likelihood estimation method to estimate the parameters involved in the proposed model. Our simulation studies numerically confirm our theoretical findings and demonstrate that the proposed model with estimated parameters can improve the fitness of clinical data.

The comparative effects of dietary monensin and propylene glycol on insulin resistance of transition dairy cows.

During the transition period, dairy cows suffer from negative energy balance due to the upcoming insulin resistance as a major metabolic disturbance. We hypothesized that providing glucose precursors for transition dairy cows may reduce the insulin resistance. In this study, 24 multiparous Holstein dairy cows were enrolled 8 weeks prior to parturition and divided into 4 equal groups, including control (Ctrl), monensin (Mo), propylene glycol (PPG), and monensin plus propylene glycol (Mo + PPG). Cows from the Mo and PPG groups received 1 mg/kg body weight (BW) of monensin, daily. Cows from the PGG group received 150 g of propylene glycol, daily. Cows from the Mo + PPG group received 1 mg/kg BW of monensin and 150 g/head of propylene glycol daily and Ctrl cows received basal diet without any supplementations. Intravenous glucose tolerance test (ivGTT) was conducted weekly from 3 weeks before to 3 weeks after parturition to evaluate the insulin resistance phenomenon. Immediately after glucose administration, glucose and insulin increased significantly, and their alterations were significant during the study. Glucose and insulin were significantly higher in the Ctrl group than in the other groups, and their levels in different pre- and post-partum periods were significantly lower in the Mo + PPG group than in the other studied groups. The results of this study represented that the supplementary feeding with propionate precursors, such as monensin and propylene glycol, reduced the insulin resistance in dairy cows during the transition period. This effect is more explicit by propylene glycol than by monensin, and the combination of both reduces insulin resistance at higher rates. The use of these dietary supplements is likely to produce more propionates as the main precursor of glucose; therefore, it reduces the negative energy balance and subsequently decreases the insulin resistance. In this regard, to reduce insulin resistance, it is recommended that dairy cows during the transition period be fed with monensin and propylene glycol supplements.

Time-Restricted Feeding Improves Glucose Tolerance in Rats, but Only When in Line With the Circadian Timing System.

Epidemiological studies indicate that shift-workers have an increased risk of type 2 diabetes mellitus (T2DM). Glucose tolerance and insulin sensitivity both are dependent on the circadian timing system (i.e., the time-of-day) and fasting duration, in rodents as well as humans. Therefore, question is whether manipulation of the circadian timing system, for example by changing the timing of feeding and fasting, is a potential preventive treatment for T2DM. Time-restricted feeding (TRF) is well-known to have profound effects on various metabolic measures, including glucose metabolism. However, experiments that directly measure the effects of TRF on glucose tolerance and/or insulin sensitivity at different time points throughout the 24 h cycle are lacking. Here we show, in rats, that TRF in line with the circadian timing system (i.e., feeding during the active phase) improves glucose tolerance during intravenous glucose tolerance tests (ivGTT) in the active phase, as lower insulin levels were observed with similar levels of glucose clearance. However, this was not the case during the inactive phase in which more insulin was released but only a slightly faster glucose clearance was observed. Contrasting, TRF out of sync with the circadian timing system (i.e., feeding during the inactive phase) worsened glucose tolerance, although only marginally, likely because of adaptation to the 4 week TRF regimen. Our results show that TRF can improve glucose metabolism, but strict adherence to the time-restricted feeding period is necessary, as outside the regular eating hours glucose tolerance is worsened.

Effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients.

OBJECTIVE: To investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis (CF) (Phe508del/Phe508del). METHODS: A standard oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed to investigate glucose metabolism and insulin secretion before and after 6-8weeks of treatment with Lumacaftor/Ivacaftor in 5 Phe508del-homozygous CF patients. The area under the curve (AUC) for glucose and insulin levels was calculated using the trapezoidal approximation. RESULTS: 5 participants were investigated. Treatment with Lumacaftor/Ivacaftor was followed by an improvement of the 2h glucose levels in 3 patients and worsening in 2 patients. Analysis of the time course of blood glucose levels during OGTT revealed an increase of the AUC in 3 of 5 patients. In response to IVGTT, acute insulin secretion improved in 2 patients and worsened in 3. CONCLUSION: The investigation could not demonstrate that treatment with Lumacaftor/Ivacaftor had a consistent impact on glucose tolerance and insulin secretion. Further adequately-powered studies examining glucose metabolism are needed to properly evaluate drug response in the endocrine pancreas and to test whether this treatment could eventually prevent the development of cystic fibrosis-related diabetes (CFRD).

Long-term feeding of high-fat plus high-fructose diet induces isolated impaired glucose tolerance and skeletal muscle insulin resistance in miniature pigs.

BACKGROUND: During the prediabetic development, the changes in ß-cell function and tissue-specific insulin resistance have been described. However, there are conflicting views in insulin secretory capacity between early clinical observation and recent proposed mathematical model. On the basis of digestive and metabolic similarities with humans, swine have great potential as an animal model to investigate the progressive mechanisms of prediabetes. The aim of this study was to investigate the insulin secretory response and tissue-specific insulin resistance in a dietary-induced prediabetic porcine model. METHODS: Adult male Taiwan Lee-Sung miniature pigs were randomized into two groups: (1) low-fat diet and (2) high-fat plus high-fructose diet (HFHF; 20.9% crude fat and 17.8% fructose). During the 12-month dietary intervention, body weights and blood glucose levels were measured monthly. Intravenous glucose tolerance test was used for measuring glucose tolerance and insulin secretory capacity. At the end of the experiment, liver and soleus muscle specimens were collected for ex vivo insulin sensitivity testing. RESULTS: The results showed that the HFHF group had obesity, hyperinsulinemia, and dyslipidemia, but normal fasting glucose levels. The HFHF pigs exhibited enhanced first- and second-phase insulin secretion and high 2-h postload glucose levels in intravenous glucose tolerance test. Furthermore, the skeletal muscle specimens from the HFHF group were desensitized to insulin stimulation as shown by the lack of AKT Ser473 phosphorylation; however, the liver specimens remained a normal response. CONCLUSIONS: In conclusion, the HFHF diet-fed pigs developed isolated impaired glucose tolerance corresponding to prediabetes with an intense insulin secretory response and skeletal muscle insulin resistance.

Lack of change in glucose metabolism in eszopiclone-treated primary insomnia patients.

STUDY OBJECTIVES: Primary insomnia (PI) may increase diabetes risk. We tested the hypothesis that the effects of PI on glucose metabolism could be improved by 2 months of pharmacological treatment. METHODS: Adult men and women meeting clinical criteria for PI were studied (n=20, body mass index 25.1±2.7 kg/m2, age 39.7±7.9) in a randomized, double-blind, placebo-controlled clinical trial. The study consisted of two 1-day inpatient admissions to a General Clinical Research Center separated by 2 months of at-home treatment with 3 mg eszopiclone or placebo. During inpatient admissions, each subject underwent two intravenous glucose tolerance tests (IVGTTs) pre- and post-treatment. Diet was controlled for micro- and macro-nutrient content and calories on the day prior to pre- and post-treatment IVGTTs. Subjects were randomized following completion of the initial IVGTT to take either placebo or eszopiclone 30 min prior to bedtime at home for 2 months. RESULTS: Two-month eszopiclone treatment did not change insulin sensitivity, glucose tolerance, or any of the sleep measures significantly, compared with placebo. Changes in glycated hemoglobin (HbA1c, clinical measure of glycemic control) were correlated with changes in diary-reported total sleep time in the eszopiclone group (r=0.66, p=0.0360), and in the combined groups' data (r=0.55, p=0.0125). Changes in polysomnography-measured wake after sleep onset, a hallmark of PI, were positively related to changes in IVGTT-derived glucose effectiveness, or non-insulin-mediated glucose uptake. CONCLUSION: Treatment with 3 mg eszopiclone for 2 months, compared with placebo, did not significantly influence either sleep or measures of diabetes risk in this preliminary study.

Abundance in proteins expressed after functional electrical stimulation cycling or arm cycling ergometry training in persons with chronic spinal cord injury.

STUDY DESIGN: Longitudinal design. OBJECTIVES: The study determined the effects of two forms of exercise training on the abundance of two proteins, (glucose transporter-4 [GLUT-4], adenosine monophosphate kinase [AMPK]) involved in glucose utilization and the transcriptional coactivator that regulates the genes involved in energy metabolism and mitochondrial biogenesis (peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha [PGC-1α]), in muscles in men with chronic motor-complete spinal cord injury (SCI). SETTINGS: Clinical trial at a Medical Center. METHODS: Nine men with chronic motor-complete SCI participated in functional electrical stimulation lower extremity cycling (FES-LEC; n = 4) or arm cycling ergometer (arm-cycling ergometer [ACE]; n = 5) 5 days/week for 16 weeks. Whole body composition was measured by dual energy X-ray absorptiometry. An intravenous glucose tolerance test was performed to measure glucose effectiveness (Sg) and insulin sensitivity (Si). Muscle biopsies of the right vastus lateralis (VL) and triceps muscles were collected one week prior to and post the exercise training intervention. RESULTS: Neither training intervention altered body composition or carbohydrate metabolism. GLUT-4 increased by 3.8 fold in the VL after FES training and increased 0.6 fold in the triceps after ACE training. PGC-1α increased by 2.3 fold in the VL after FES training and 3.8 fold in the triceps after ACE training. AMPK increased by 3.4 fold in the VL after FES training and in the triceps after ACE training. CONCLUSION: FES-LEC and ACE training were associated with greater protein expressions in the trained muscles by effectively influencing the abundance of GLUT-4, AMPK and PGC-1α. Thus, FES-LEC training of paralyzed muscle can modulate protein expression similar to that of trained and innervated muscle.