Insulin Sensitivity In People Research Articles

Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease

Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N= 14); (2) obese with normal IHTG content (OB-NL; N= 28); and (3) obese with NAFLD (OB-NAFLD; N= 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (−2.7 ± 8.2% in the placebo vs. −20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

The Effect of Vitamin D Supplementation on Insulin Sensitivity: A Systematic Review and Meta-analysis.

Vitamin D has been suggested to affect peripheral insulin sensitivity. Evidence regarding the effect of vitamin D supplementation on insulin sensitivity is still conflicting. This meta-analysis aimed to assess the effect of vitamin D supplementation on insulin sensitivity in humans with or at risk for insulin resistance. PubMed, Web of Science, Embase, CINAHL, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) from 1980 until 31 December 2018 reporting treatment effects of vitamin D supplementation on insulin sensitivity. The main outcome of interest was the change in insulin sensitivity, derived from the gold standard hyperinsulinemic-euglycemic clamp or the Matsuda index derived from the oral glucose tolerance test and insulin sensitivity index from intravenous glucose tolerance test. We extracted data on the standardized mean difference between the vitamin D treatment and placebo groups in change from baseline insulin sensitivity. Eighteen RCTs were included in this meta-analysis comparing vitamin D supplementation (n = 612) with placebo (n = 608). Vitamin D supplementation had no effect on insulin sensitivity (standardized mean difference -0.01, 95% CI -0.12, 0.10; P = 0.87, I 2 = 0%). Visual inspection of funnel plot symmetry did not suggest potential publication bias. The number of individuals who participated in the included studies was relatively small, possibly due to the invasive character of the measurement (e.g., clamp). This meta-analysis provides no evidence that vitamin D supplementation has a beneficial effect on peripheral insulin sensitivity in people with or at risk for insulin resistance.

Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes.

Incretin effect-the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route-is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans. Thirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (β-GS), glucose-induced potentiation (PGLU) and incretin-induced potentiation (PINCR); the oral glucose sensitivity index was used to estimate insulin sensitivity. Lipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m2 on OGTT and from 29nmol/m2 [26] to 57nmol/m2 [30] on ISO) and induced insulin resistance. PINCR decreased from 1.6 [1.1] to 1.3 [0.1] (p < 0.05). β-GS, PGLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change β-GS, PINCR, PGLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes. Raising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.

Carbohydrate metabolism and gene expression of sirtuin 1 in healthy subjects after Sacha inchi oil supplementation: a randomized trial

The postprandial stage is related to cardiovascular risk and it depends on the type of meal consumed. We study the effects of Sacha inchi oil on the postprandial glycemic state caused by meals rich in saturated fat. A double blind randomized trial in which 42 adult men ingested two breakfasts rich in saturated fat, one of them containing additionally 15 mL of Sacha inchi oil. Blood samples were obtained before or after 1 and 4 hours post-ingestion to quantify glucose, insulin and lipid profile in serum. The insulinogenic and sensitivity indices were calculated and the expression of sirtuin-1 in circulating mononuclear cells by qPCR was determined. Oil addition attenuated the increase of glucose in 16 (38.1%) participants. This group showed a higher concentration of fasting triacylglycerides and sirtuin-1 expression at 4 hours post-Sacha inchi oil correlated with glucose at the same time (r = -0.724; p = 0.012), and with postprandial insulin sensitivity (r = 0.636; p = 0.035). The addition of Sacha inchi oil to a highly fatty meal improves insulin sensitivity in people with higher basal triglyceridemia and higher glycemic responses after a fat load. Under these conditions, sirtuin-1 expression correlates with postprandial insulin sensitivity.

418 - Odd-Chain Fatty Acids Predict Insulin Sensitivity in People with T2DM and Protect HepG2 Cells from Palmitate-Induced Insulin Resistance Via PPARα

Lipid-induced dysfunction of the liver, especially steatohepatitis, is becoming increasingly prevalent and may be an important link between obesity and type 2 diabetes (T2DM). Elevated circulating saturated fatty acids contribute to steatohepatitis and T2DM while other plasma free fatty acids appear protective. Activated PPARα is involved in regulating hepatic lipid accumulation by upregulating genes responsible for fatty acid transport and metabolism. We examined the hypothesis that specific fatty acids predict insulin sensitivity in T2DM patients and modulate risk of steatohepatitis by activating PPARα. The plasma fatty acid profile of patients with T2DM (n=43) and healthy control subjects (n=45) was analysed using gas chromatography. An in vitro model of terminally differentiated (d)HepG2 cells was used to determine the mechanism of effect of novel protective fatty acids on insulin resistance and hepatocyte dysfunction. Plasma levels of odd-chain saturated fatty acids (OCSFA) predicted fasting plasma glucose in a multiple regression model, after adjusting for age, BMI and gender. OCSFA protected dHepG2 cells from palmitate-induced insulin resistance and cellular dysfunction; by increasing cellular glycogen content, cellular monounsaturated fatty acid (MUFA) concentration and reducing output of glucose and TNFα. The PPARα antagonist GW6471 blocked the increase of MUFA due to OCSFA in palmitate-exposed hepatocytes. Furthermore, OCSFA increased PPARα activity in palmitate-exposed hepatocytes more than the PPARα agonist fenofibrate. OCSFA induced upregulation of the PPARα targets, stearoyl Co-A desaturase 1 and fatty acid synthase in palmitate-exposed hepatocytes. In summary, OCSFA inversely associates with insulin resistance and promotes MUFA accumulation via a PPARα-dependent pathway, exerting a protective effect against hepatocyte dysfunction.

A dose-response evaluation of freeze-dried strawberries independent of fiber content on metabolic indices in abdominally obese individuals with insulin resistance in a randomized, single-blinded, diet-controlled crossover trial.

This study evaluated the dose-response relationship of strawberries, an anthocyanin-rich fruit, on postprandial glucose and insulin concentrations in individuals with insulin resistance (IR), including changes in plasma anthocyanins, markers of oxidative stress, and inflammation. In a randomized controlled, four-arm, dose-response, crossover trial, 21 adults with IR consumed a high-carbohydrate, high-fat meal with one of four beverages containing 0 g freeze-dried whole strawberry powder (0g FDS, control), 10, 20, or 40 g FDS, controlled for fiber. Blood was collected at 0 min and at 30 min intervals postmeal until 2 h, then hourly until 6 h. Postmeal insulin concentrations (6 h) were significantly reduced after the 40-g FDS beverage compared to other beverages (p<0.05). Postmeal 6 h glucose concentrations were not different, although mean insulin:glucose ratio was significantly different among beverages (p<0.05). Pelargonidin-glucuronide was inversely associated with mean insulin concentrations after the 20 and 40 g FDS (p<0.05). Oxidized low-density lipoprotein was reduced after 20 g FDS (p<0.05) and IL-6 was not different among treatments. Strawberry intake reduced the insulin demand to manage postmeal glucose in obese individuals with IR, which was related to plasma anthocyanin/pelargonidin concentrations. The data support a role of strawberries in improving insulin sensitivity in people with IR.

Ascorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: Findings of a randomized controlled study

Aim/hypothesisSkeletal muscle insulin resistance and oxidative stress are characteristic metabolic disturbances in people with type 2 diabetes. Studies in insulin resistant rodents show an improvement in skeletal muscle insulin sensitivity and oxidative stress following antioxidant supplementation. We therefore investigated the potential ameliorative effects of antioxidant ascorbic acid (AA) supplementation on skeletal muscle insulin sensitivity and oxidative stress in people with type 2 diabetes. MethodsParticipants with stable glucose control commenced a randomized cross-over study involving four months of AA (2×500mg/day) or placebo supplementation. Insulin sensitivity was assessed using a hyperinsulinaemic, euglycaemic clamp coupled with infusion of 6,6-D2 glucose. Muscle biopsies were measured for AA concentration and oxidative stress markers that included basal measures (2′,7′-dichlorofluorescin [DCFH] oxidation, ratio of reduced-to-oxidized glutathione [GSH/GSSG] and F2-Isoprostanes) and insulin-stimulated measures (DCFH oxidation). Antioxidant concentrations, citrate synthase activity and protein abundances of sodium-dependent vitamin C transporter 2 (SVCT2), total Akt and phosphorylated Akt (ser473) were also measured in muscle samples. ResultsAA supplementation significantly increased insulin-mediated glucose disposal (delta rate of glucose disappearance; ∆Rd) (p=0.009), peripheral insulin-sensitivity index (p=0.046), skeletal muscle AA concentration (p=0.017) and muscle SVCT2 protein expression (p=0.008); but significantly decreased skeletal muscle DCFH oxidation during hyperinsulinaemia (p=0.007) when compared with placebo. Total superoxide dismutase activity was also lower following AA supplementation when compared with placebo (p=0.006). Basal oxidative stress markers, citrate synthase activity, endogenous glucose production, HbA1C and muscle Akt expression were not significantly altered by AA supplementation. Conclusions/interpretationIn summary, oral AA supplementation ameliorates skeletal muscle oxidative stress during hyperinsulinaemia and improves insulin-mediated glucose disposal in people with type 2 diabetes. Findings implicate AA supplementation as a potentially inexpensive, convenient, and effective adjunct therapy in the treatment of insulin resistance in people with type 2 diabetes.

Development and Validation of a Method to Estimate Insulin Sensitivity in Patients With and Without Type 1 Diabetes.

People with type 1 diabetes (T1D) have markedly reduced insulin sensitivity (IS) compared to their nondiabetic counterparts, and reduced IS is linked to higher cardiovascular risk. This study aimed to develop and validate an improved method for estimating IS in people with T1D. Prospective cohort. Adults (36 with T1D, 41 nondiabetic) were recruited from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study for measurement of IS by hyperinsulinemic-euglycemic clamp to develop a clinically useful IS prediction equation (eIS) for T1D and nondiabetic individuals. These equations were then compared with previously published equations from the SEARCH and Pittsburgh Epidemiology of Diabetes Complications studies for the ability to predict measured IS in test sets of adults and adolescents from independent clamp studies. None. Comparison of clamp-measured IS to estimated IS. The best-fit prediction model (eIS) differed by diabetes status and included waist circumference, triglycerides, adiponectin, and diastolic blood pressure in all CACTI adults and insulin dose in adults with T1D (adjusted R(2) = 0.64) or fasting glucose and hemoglobin A1c (HbA1c) in nondiabetic adults (adjusted R(2) = 0.63). The eIS highly correlated with clamp-measured IS in all of the non-CACTI comparison populations (r = 0.83, P = .0002 in T1D adults; r = 0.71, P = .01 in nondiabetic adults; r = 0.44, P = .008 in T1D adolescents; r = 0.44, P = .006 in nondiabetic adolescents). eIS performed better than previous equations for estimating IS in individuals with and without T1D. These equations could simplify point-of-care assessment of IS to identify patients who could benefit from targeted intervention.

An evaluation of the DEXLIFE ‘self-selected’ lifestyle intervention aimed at improving insulin sensitivity in people at risk of developing type 2 diabetes: study protocol for a randomised controlled trial

BackgroundWith the global escalation of type 2 diabetes and evidence consistently showing that its onset can be prevented or delayed by changing lifestyle behaviours, there is an urgent need to translate practical, affordable and acceptable interventions from the research setting into the real world. One such approach to lifestyle interventions might be the introduction of a programme in which the individual is provided with choice and facilitated to ‘self-select’ an exercise programme. Previous research has shown that this is likely to be less resource intensive, an essential requirement for success outside the controlled research environment, while at the same time promoting positive responses relating to adherence, competence and self-efficacy, essential attributes for long-term success. Through a two-group parallel-randomised controlled trial, this study aims to assess the clinical and psychological impact of the DEXLIFE ‘self-selected’ lifestyle modification programme in adults at risk of developing type 2 diabetes.Methods/designA total of 360 subjects at risk of developing type 2 diabetes are randomly assigned in a 1:3 ratio to a control (n = 90) or intervention arm (n = 270). Randomization is stratified by age, sex and body mass index. The control arm receives general information on lifestyle and diabetes risk. The intervention group participate in a 12 week ‘self-selected’ supervised exercise training programme accompanied with dietary advice to improve food choices. Participants are given access to Dublin City University Sport (an on-campus gym) and asked to perform four exercise classes per week. Dublin City University Sport offers over 50 classes per week, many of which are medically supervised. If weight loss is indicated, reduction in total calorie intake by 600 kcal/day is advised. Common to all food plans is <10 % saturated fat intake, as well as a dietary fibre intake of >15 g/1000 kcal.Insulin sensitivity is the primary outcome measure. Secondary outcome measures include glucose function, fitness, body composition, anthropometrics, heart rate variability, lipid profiles, blood pressure, physical activity levels, dietary intake and quality of life.Discussion"Self-selected" lifestyle intervention has not previously been evaluated in type 2 diabetes prevention and if shown to be successful could be implemented in practice immediately.Trial registrationCurrent Controlled Trials: ISRCTN66987085.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-1042-1) contains supplementary material, which is available to authorized users.

Strawberry Polyphenols and Insulin Resistance: a dose‐response study in Obese Individuals with Insulin Resistance

Insulin resistance is a major risk factor for developing type 2 diabetes mellitus (T2DM). Epidemiological data suggest that dietary anthocyanins (ACN) are associated with lower insulin resistance (IR) and T2DM risk. The present study assessed the effects of strawberries, a major dietary source of ACN, on acute insulin and glucose responses in individuals with IR. In a randomized 4‐arm crossover study, 23 obese adults consumed beverages containing freeze‐dried strawberry powder (FDS) at 4 levels [0, 10, 20, or 40 g corresponding to ~0 to 368 umol ACN]. The FDS beverages were fiber controlled and served with a standard meal with blood collected before and for 6 h after meal consumption on 4 occasions. Mean 6 h insulin was significantly lowered after consuming the 40 g FDS beverage/meal compared to all other beverages (p&lt;0.05). No differences were observed in 6 h glucose responses, although the magnitude of increase from baseline was significantly lower (~29%) after the 40 g FDS beverage compared to other beverages (p&lt;0.05). In adults with higher fasting insulin and greater IR, significant reductions in peak post meal insulin was apparent with 20 g and 40 g FDS beverages (p&lt;0.05), whereas in those with a lesser degree of IR the 40 g FDS reduced peak post meal insulin. Oxidative stress was not different between groups, whereas IL‐6 was lowest after the 10 g FDS beverage. FDS ACN increased in plasma dose‐dependently reaching peak concentrations between 130 and 189 ± 45 min. These data support the view that strawberries have a role in improving insulin sensitivity in people with insulin resistance. Supported by CA Strawberry Commission, CA Dept of Food and Ag, Sacramento, CA. USA

Abstract 14007: Insulin Resistance Expressed by Homa2 Predicts Risk for Recurrent Coronary Events in Post Infarction Patients

We investigated risk for recurrent coronary events associated with insulin resistance in post infarction patients from the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) study. The association between insulin resistance expressed by Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR) and risk for recurrent coronary events was investigated in a cohort of 1,035 patients evaluated 2 months after myocardial infarction with an average follow-up of 26 months. The end point for the study was recurrent coronary event defined as death, nonfatal myocardial infarction and unstable angina whichever occurred first. We used time dependent survival analysis and Cox proportional hazards regression method to determine the association between HOMA2 categorized as high &gt;75th percentile and endpoints after adjustment for relevant clinical covariates. High HOMA2-IR defined as in fourth quartile(&gt; 2.4) was associated with increased risk for recurrent coronary events (hazard ratio [HR] 1.54; 95% confidence interval [CI] 1.10-2.14; P &lt;0.01) after adjustment for: age, gender, diabetes, prior myocardial infarction, pulmonary congestion on chest roentgenogram, ejection fraction&lt; 0.3, PTCA and CABG. The interaction between HOMA2-IR and diabetes status regarding recurrent coronary events was not statistically significant. The highest risk of cardiac events was observed in non-obese patients (BMI&lt;=30kg/m2) with high HOMA2-IR (hazard ratio [HR] 1.55; 95% confidence interval [CI] 1.05-2.23; P &lt;0.05). Patients with High HOMA2-IR had higher plasma level of fibrinogen, PAI-1, von Willebrand factor, triglyceride and apolipoprotein B. Insulin resistance predicts recurrence of coronary events in post-infarction population. HOMA2-IR and BMI are useful parameters in clinical practice to stratify risk. Multilevel intervention to increase insulin sensitivity in people after myocardial infarction may modify clinical outcome.

Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes.

To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥ 20 μg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 μg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. Estimated insulin sensitivity was significantly higher at both baseline (4.6 ± 1.2 vs 3.4 ± 1.7; P = 0.002) and follow-up (5.2 ± 1.9 vs. 3.5 ± 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.

Systematic review of randomised controlled trials of the effects of caffeine or caffeinated drinks on blood glucose concentrations and insulin sensitivity in people with diabetes mellitus

Compounds other than macronutrients have been shown to influence blood glucose concentrations and insulin sensitivity in people with diabetes, with caffeine being one such substance. The present study systematically reviewed the evidence of the effects of caffeine on blood glucose concentrations and/or insulin sensitivity in people with diabetes. Four databases, including MEDLINE and EMBASE, were searched up to 1 February 2012. Randomised controlled trials (RCTs) investigating the effects of caffeine on blood glucose and/or insulin sensitivity in humans, diagnosed with type I, type II or gestational diabetes mellitus (GDM), were included. Quality assessment and data extraction were conducted and agreed by both authors. Of 253 articles retrieved, nine trials (134 participants) were identified. Trials in people with type II diabetes demonstrated that the ingestion of caffeine (approximately 200-500mg) significantly increased blood glucose concentrations by 16-28% of the area under the curve (AUC) and insulin concentrations by 19-48% of the AUC when taken prior to a glucose load, at the same time as decreasing insulin sensitivity by 14-37%. In type I diabetes, trials indicated enhanced recognition and a reduced duration of hypoglycaemic episodes following ingestion of 400-500mg caffeine, without altering glycated haemoglobin. In GDM, a single trial demonstrated that approximately 200mg of caffeine induced a decrease in insulin sensitivity by 18% and a subsequent increase in blood glucose concentrations by 19% of the AUC. Evidence indicates a negative effect of caffeine intake on blood glucose control in individuals with type II diabetes, as replicated in a single trial in GDM. Larger-scale RCTs of longer duration are needed to determine the effects of timing and dose. Early indications of a reduced duration and an improved awareness of hypoglycaemia in type I diabetes require further confirmation.

Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

BackgroundObesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs), for 6 months in rodent models restores insulin receptor function and insulin sensitivity.MethodsThis 12-week double-blind, randomized, placebo (PL)-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI), doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2). The study included non-DM2 controls (n = 15), and DM2 subjects randomized to PL (n = 13) or doxycycline 100 mg twice daily (MMPI; n = 11). All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment.ResultsThere was a significant decrease in inflammatory markers C-reactive protein (P < 0.05) and myeloperoxidase (P = 0.01) in the MMPI but not PL group. The MMPI also significantly increased skeletal muscle activated/total insulin signaling mediators: 3’phosphoinositide kinase-1 (PDK1) (p < 0.03), protein kinase B (PKB/Akt) (p < 0.004), and glycogen synthase kinase 3ß (GSK3ß) (p < 0.03).ConclusionsThis study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes.Trial RegistrationClinicaltrials.gov NCT01375491

A cross-over study of the acute effects of espresso coffee on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus

The objective was to determine the effect of a single dose of espresso caffeinated coffee, decaffeinated coffee, or water on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus. Eighteen participants who were habitual coffee drinkers, were studied using a random-order cross-over design. After a fasting blood sample participants consumed either a double-shot black espresso coffee, decaffeinated coffee, or hot water. The main outcomes were area under the curve (AUC) glucose and insulin, and insulin sensitivity (Matsuda index) during a 75 g oral glucose tolerance test (OGTT) performed one hour later. Other outcomes were change in glucose and insulin and also the insulinogenic index (IGI) and disposition index (DI). AUC glucose was marginally different between beverages (P=.06) being greater following caffeinated coffee than water, mean difference 104 mmol/L/180 min (95% CI 0.1 to 198.1, P=.031), or decaffeinated coffee, mean difference 92.1 mmol/L/180 min (95% CI −1.9 to 186.1, P=.055). There was no difference in AUC insulin (P=.87) or insulin sensitivity (P=.47), nor in change in glucose or insulin over the hour following beverage consumption. There was a marginal difference in IGI between beverages (P=.097) with coffee having a lower incremental increase in insulin/glucose than water (P=.037) though no difference between coffee and decaffeinated coffee (P=.54) and no difference in DI (P=.23). Black espresso coffee in people with type 2 diabetes mellitus results in a marginally greater excursion of glucose during a following OGTT compared with water or decaffeinated coffee. This effect does not appear to be mediated by changes in insulin sensitivity.

Recombinant Human Leptin Treatment Does Not Improve Insulin Action in Obese Subjects With Type 2 Diabetes

OBJECTIVELeptin therapy improves insulin sensitivity in people with leptin deficiency, but it is not known whether it improves insulin action in people who are not leptin deficient. The purpose of the current study was to determine whether leptin treatment has weight loss–independent effects on insulin action in obese subjects with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted a randomized, placebo-controlled trial in obese subjects (BMI: 35.4 ± 0.6 kg/m2; mean ± SE) with newly diagnosed type 2 diabetes. Subjects were randomized to treatment with placebo (saline), low-dose (30 mg/day), or high-dose (80 mg/day) recombinant methionyl human (r-Met hu) leptin for 14 days. Multiorgan insulin sensitivity before and after treatment was evaluated by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions to measure glucose, glycerol, and fatty acid kinetics.RESULTSLow-dose and high-dose leptin treatment resulted in a threefold (P < 0.01) and 150-fold (P < 0.001) increase in basal plasma leptin concentrations, respectively. However, neither low-dose nor high-dose therapy had an effect on insulin-mediated suppression of glucose, glycerol, or palmitate rates of appearance into plasma compared with placebo. In addition, leptin treatment did not increase insulin-mediated stimulation of glucose disposal compared with placebo (14.3 ± 3.1, 18.4 ± 3.6, 16.7 ± 2.4 vs. 17.5 ± 2.5, 20.7 ± 3.0, 19.1 ± 3.3 μmol/kg body wt/min before vs. after treatment in the placebo, low-dose, and high-dose leptin groups, respectively).CONCLUSIONSr-Met hu leptin does not have weight loss–independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes.

Reduced Plasma Glucose and Leptin After 12 Weeks of Functional Electrical Stimulation–Rowing Exercise Training in Spinal Cord Injury Patients

Jeon JY, Hettinga D, Steadward RD, Wheeler GD, Bell G, Harber V. Reduced plasma glucose and leptin after 12 weeks of functional electrical stimulation–rowing exercise training in spinal cord injury patients. Objective: To investigate the effects of exercise training with a functional electrical stimulation (FES) rowing machine on insulin resistance, plasma leptin levels, and body composition in people with spinal cord injury (SCI). Design: Experimental study. Setting: A fitness and research center for people with disabilities. Participants: Healthy male participants with paraplegia (N=6) participated in the study (mean age, 48.6±6y; mean weight, 70.06±3.28kg; injury levels between T4-5 and T10). Interventions: Twelve weeks of FES-rowing exercise training 3 to 4 times a week (600–800kcal). Main Outcome Measures: Peak oxygen consumption, plasma leptin, insulin, and glucose levels, insulin sensitivity, body composition. Results: Twelve weeks of FES-rowing training improved aerobic fitness significantly ( P=.048). In addition, plasma glucose and leptin levels were significantly decreased after exercise training by 10% and 28% ( P<.028), respectively. A trend toward fat mass reduction was seen in 4 of the 6 subjects; this change did not reach statistical significance ( P=.08). Conclusion: A 12-week training program that included FES rowing improved aerobic fitness and fasting glucose and leptin levels in the absence of significant change to body composition, fasting insulin levels, or calculated insulin sensitivity in people with SCI.

Effectiveness of energy-restricted diets with different protein:carbohydrate ratios: the relationship to insulin sensitivity

Insulin sensitivity could determine the effectiveness of weight-loss diets with different protein:carbohydrate ratios. Our aim was to evaluate whether or not energy-restricted diets with different protein:carbohydrate ratios in obese individuals with (IR) or without (IS) insulin resistance could lead to differences in weight loss or insulin sensitivity. Prospective, randomized, clinical intervention study. Thirty-six obese patients, allocated to the IR or IS group after a 75 g oral glucose tolerance test and calculation of the homeostasis model assessment of insulin resistance (HOMA) index, were assigned to follow an energy-restricted diet with either 40 % carbohydrate/30 % protein/30 % fat (diet A) or 55 % carbohydrate/15 % protein/30 % fat (diet B) and followed up to 16 weeks. Twenty-one IR and fifteen IS patients were randomized to diet A or B. After 16 weeks, there was no difference in weight loss between diets A and B in each group. Glucose and insulin levels and HOMA were significantly reduced at 16 weeks, but no differences related to the type of diet were detected either in the IR or the IS group. Varying the macronutrient composition of a hypoenergetic diet, regarding the percentage protein:carbohydrate ratio, did not produce different weight loss or result in an improvement in insulin sensitivity in people with or without insulin resistance.

Insulin-Sensitivity Response to a Single Bout of Resistive Exercise in Type 1 Diabetes Mellitus

Little is known about the acute effects of resistance exercise on insulin sensitivity in people with type 1 diabetes. Repeated-measures design with 2 independent variables: group (exercise and nonexercise control) and time (preexercise and 12 and 36 h postexercise). General Clinical Research Center, Temple University Hospital, Philadelphia, PA. 14 physically active subjects (11 men and 3 women) with type 1 diabetes. The exercise group completed 5 sets of 6 repetitions of strenuous (80% 1-RM) quadriceps and hamstring exercises while the control group performed only activities of daily living. Insulin sensitivity was assessed with the euglycemic-hyperinsulinemic-clamp technique preexercise and 12 and 36 h postexercise. Insulin-sensitivity values were not significantly different between the exercise and control groups (P = .92) or over time (P = .67). A single bout of strenuous resistance exercise does not alter insulin sensitivity in people with type 1 diabetes.