Insulin Sensitivity In Individuals Research Articles

Improvements in glucose tolerance in obese males with abnormal glucose tolerance following 10 days of aerobic exercise

Background. Aerobic exercise training has been shown to produce beneficial changes in glucose tolerance and insulin sensitivity in obese individuals if performed at high enough intensities and/or durations. We examined the effects of a moderate intensity, short-term exercise training protocol on glucose tolerance in obese males with glucose intolerance. Methods. Fourteen abdominally obese, sedentary males with normal glucose tolerance (NGT; n = 7) and abnormal glucose tolerance (AGT; n = 7) completed 40 min of exercise bouts for 10 consecutive days at approximately 75% of age-predicted maximum heart rate. Fasting glucose and insulin levels, and glucose tolerance and insulin response to glucose were measured before and after the training period. Results. Participants did not experience significant mass loss during the 10-day investigation. Individuals in the AGT group experienced significant ( P < 0.05) improvement in glucose tolerance [glucose area: 1,763.67 (255.98) mmol L −1 × 120 min −1 vs. 1,682.98 (266.91) mmol L −1 × 120 min −1] and fasting insulin levels [44.57 (7.58) μU mL −1 vs. 36.14 (3.97) μU mL −1] as a result of training. Significant ( P < 0.05) reductions in fasting glucose concentrations [5.82 (0.19) mmol L −1 vs. 5.42 (0.18) mmol L −1] and a decrease in fasting insulin concentrations [44.71 (9.39) μU mL −1 vs. 35.0 (7.15) μU mL −1; P = 0.064] were observed in the NGT group following the training period. Conclusions. The data suggest that moderate, short-term exercise without concomitant mass loss is effective in improving glucose tolerance and insulin response to a glucose load in obese males with abnormal glucose tolerance.

Inflammation in the prediabetic state is related to increased insulin resistance rather than decreased insulin secretion.

Elevated levels of proinflammatory proteins are predictive of both cardiovascular (CV) disease and type 2 diabetes. Previously, atherogenic changes in traditional CV risk factors in the prediabetic state were mainly seen in insulin-resistant subjects rather than in those with a predominant defect in insulin secretion. We studied in prediabetic individuals from the Insulin Resistance Atherosclerosis Study (IRAS) the relation of C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-1, and fibrinogen to defects in insulin sensitivity (SI) and first-phase insulin secretion, respectively, as assessed using a frequently sampled intravenous glucose tolerance test. One hundred forty-eight of 906 (16.3%) nondiabetic individuals developed diabetes after a mean follow-up of 5.2 years. Prediabetic individuals who were insulin resistant had higher levels of PAI-1 (mean [95% CI], 25.83 ng/mL [22.42 to 29.77] versus 16.31 ng/mL [12.56 to 21.18]; P=0.003) and CRP (mean [95% CI], 2.88 mg/L [2.33 to 3.56] versus 1.68 mg/L [1.13 to 2.49]; P=0.018) than insulin-sensitive individuals, but individuals with decreased acute insulin response tended to have lower rather than higher levels of inflammatory proteins compared with those with high insulin secretion. Prediabetic subjects who were predominantly insulin resistant had higher levels of inflammatory proteins compared with both prediabetic subjects with decreased insulin secretion as well as nonconverters. By contrast, prediabetic subjects with a predominant defect in first-phase insulin secretion had levels of inflammatory proteins indistinguishable from those in nonconverters. We have shown an increased proinflammatory state in prediabetic individuals who are predominantly insulin resistant but not in those with a primary defect in beta-cell function. These results provide additional evidence that prediabetic subjects may be at an increased risk of heart disease, and this risk seems to be restricted to subjects with high insulin resistance.

Glycemic load and chronic disease.

The glycemic index (GI) has proven to be a useful nutritional concept, providing new insights into the relationship between foods and chronic disease. Observational studies suggest that diets with a high glycemic load (GI x carbohydrate content) are independently associated with increased risk of type 2 diabetes and cardiovascular disease. Postprandial hyperglycemia plays a direct pathogenic role in the disease process. Lower glucose and insulin levels are associated with improved risk profile, including high-density lipoprotein cholesterol, glycosylated proteins, oxidative status, hemostatic variables, and endothelial function. Limited evidence suggests that a low-GI diet may also protect against obesity, colon cancer, and breast cancer. Diets with a high glycemic load may affect health differently in insulin-resistant and insulin-sensitive individuals. Improvements in postprandial hyperglycemia can be brought about by manipulating either the type (i.e., GI) or amount of dietary carbohydrate, or both; at present, the GI appears to be more effective.

EXERCISE CARBOHYDRATE UTILIZATION IN INSULIN-RESISTANT AND INSULIN-SENSITIVE WOMEN MATCHED FOR BODY FATNESS

Insulin resistance (IR) is characterized by reduced insulin-mediated glucose uptake from the blood. Studies in vitro suggest that IR muscle is not resistant to contraction-mediated glucose uptake (i.e. exercise), but studies in vivo are lacking. PURPOSE To compare blood glucose uptake and total carbohydrate utilization during exercise in IR and insulin-sensitive (IS) women while controlling for body fatness and habitual physical activity. We hypothesized that, total carbohydrate utilization during exercise would be the the same in IR and IS individuals METHODS 12 overweight, sedentary but otherwise healthy women aged 22–45 participated in the study. Insulin resistance was determined by incorporating glucose and insulin responses to an oral glucose load into a mathematical model (composite insulin sensitivity index, C-ISI). The women were divided into 2 groups (n = 6): insulin-resistant (IR, BMI = 28.5 ± 1.6, %body fat = 38.4 ± 3.5, C-ISI = 3.0 ± 0.7) and insulin sensitive (IS,BMI = 27.2 ± 1.9,%body fat 44.6 ± 4.4, C-ISI = 7.7 ± 0.9). Blood glucose uptake, carbohydrate oxidation, and estimated muscle glycogen utilization were assessed using stable isotope dilution and indirect calorimetry during 50 minutes of treadmill walking at 45% VO2max. RESULTS Insulin concentrations were significantly higher in IR at rest (IR = 85.85 pM ± 40.66, IS = 44.81 pM ± 17.19) and remained higher during exercise (IR = 68.94 pM ± 11.45, IS = 33.28 pM ± 1.77). Mean carbohydrate oxidation (CHOox g/min) was significantly higher in IS(0.75 ± 0.14) compared to the IR(0.51 ± 0.14) group during exercise (p < .05). Blood glucose, lactate and FFA concentrations were similar at rest and during exercise. CONCLUSION These data suggest that, when body fatness and physical activity are matched, total carbohydrate utilization during exercise is significantly lower in IR women compared to IS. Group differences in blood glucose kinetics and/or muscle glycogen utilization may explain difference seen in total carbohydrate oxidation. Supported by UMASS/Baystate CBRP.

BMI AFFECTS THE LEPTIN RESPONSE TO EXERCISE TRAINING

Serum leptin and insulin levels are higher in obese (OB) than normal weight (NW) individuals. Moreover, leptin and insulin may affect lipid and glucose metabolism through a bi-directional feedback loop. Exercise training (ET) reduces insulin levels and improves insulin sensitivity in overweight (OW) and OB individuals; however, the effect on leptin remains ambiguous. It is therefore conceivable that the initial level of adiposity may alter the leptin response to ET. PURPOSE To examine the effects of BMI on the leptin response to ET. METHODS 119 sedentary individuals exercised 4d/wk for 50 min at 60–85% HRmax for six months. For statistical analysis, individuals were categorized according to BMI: NW (BMI ≤ 25, n = 39), OW (BMI = 25.1–29.9, n = 43), and OB (BMI ≥ 30, n = 37). RESULTS At baseline, OB had higher leptin (OB 19.1 ± 13.0 vs. OW 14.8 ± 13.8 and NW 7.9 ± 6.8ng/ml, p < 0.05), insulin (OB 11.2 ± 14.3 vs. NW 5.2 ± 2.9μU/ml, p < 0.05) and %fat (OB 27.5 ± 5.3 vs. OW 22.1 ± 5.2 and NW 19.0 ± 4.8%, p < 0.05). After ET, VO2max increased in all groups (NW 34.8 ± 7.7 vs. 38.0 ± 7.8, OW 32.8 ± 7.4 vs. 36.1 ± 9.6, OB 27.9 ± 6.7 vs. 31.1 ± 7.6 ml/kg/min, p < 0.05). The NW decreased %fat (19.0 ± 4.8 vs. 17.6 ± 4.1%, p < 0.05). The OW decreased leptin by 23.7% (14.8 ± 13.8 vs. 11.3 ± 8.5 ng/ml, p < 0.05) and body weight (BW) by 1.3kg (80.2 ± 9.2 vs. 78.9 ± 8.6 kg, p < 0.05) from baseline. The OB decreased insulin by 32% (11.2 ± 14.3 vs. 7.6 ± 4.2μU/ml, p < 0.05), %fat (27.5 ± 5.3 vs. 26.4 ± 4.6%, p < 0.05), and BW by 2.0kg (99.3 ± 14.3 vs. 97.3 ± 13.3kg, p < 0.05) from baseline, while leptin was unchanged (20.9 ± 13.5 vs. 21.0 ± 16.8 ng/ml). CONCLUSIONS Six months of ET significantly reduced BW in both the OW and OB groups, but only the OW significantly decreased leptin. This suggests that, at least in the OB state, factors other than adiposity may have influenced the leptin response to ET. The decrease in insulin observed in the OB may have altered the bi-directional feedback loop, opposing the expected reduction in leptin due to exercise induced weight loss.

Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance

Peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1 (PGC-1) regulates glucose metabolism and energy expenditure and, thus, potentially insulin sensitivity. We examined the expression of PGC-1, PPARγ, insulin receptor substrate-1 (IRS-1), glucose transporter isoform-4 (GLUT-4), and mitochondrial uncoupling protein-1 (UCP-1) in adipose tissue and skeletal muscle from non-obese, non-diabetic insulin-resistant, and insulin-sensitive individuals. PGC-1, both mRNA and protein, was expressed in human adipose tissue and the expression was significantly reduced in insulin-resistant subjects. The expression of PGC-1 correlated with the mRNA levels of IRS-1, GLUT-4, and UCP-1 in adipose tissue. Furthermore, the adipose tissue expression of PGC-1 and IRS-1 correlated with insulin action in vivo. In contrast, no differential expression of PGC-1, GLUT-4, or IRS-1 was found in the skeletal muscle of insulin-resistant vs insulin-sensitive subjects. The findings suggest that PGC-1 may be involved in the differential gene expression and regulation between adipose tissue and skeletal muscle. The combined reduction of PGC-1 and insulin signaling molecules in adipose tissue implicates adipose tissue dysfunction which, in turn, can impair the systemic insulin response in the insulin-resistant subjects.

The relationship between insulin resistance and cardiovascular risk factors in overweight/obese non-diabetic Asian adults: the 1992 Singapore National Health Survey

Insulin resistance (IR) is associated with cardiovascular risk factors including hypertension, dyslipidemia, glucose intolerance and hyperuricemia. The relationship between IR and these cardiovascular risk factors in obese non-diabetic individuals is not well studied. We explore this relationship by comparing the cardiovascular risk factors among insulin-sensitive and insulin-resistant overweight/obese non-diabetic Asian adults in the 1992 National Health Survey of Singapore. A total of 3568 subjects were examined in the survey, which involved a combination of disproportionate stratified sampling and systematic sampling. Anthropometric measurements, level of physical activity, blood pressure, insulin, lipid profile, uric acid and standard 75 g oral glucose tolerance test were performed after a 10 h overnight fast. Subjects with diabetes were excluded from the analysis. Homeostasis model assessment (HOMA) was used to assess insulin sensitivity. Relative LDL size was derived from the formula LDL/ApoB. We defined insulin-sensitive individuals as having a HOMA value <1.479 (below median in individuals without diabetes; n=3226) and overweight/obesity as body mass index (BMI) >or=25.0 kg/m(2). There were 156 insulin-sensitive (S) and 679 insulin-resistant (R) overweight/obese individuals, respectively. The groups did not differ in terms of gender and ethnic distribution and level of physical activity. However, subjects in group S were younger than those in group R (mean+/-s.d.; 40.1+/-12.1 vs 42.4+/-12.7 y; P<0.05). Group R individuals were also slightly more obese globally and centrally than group S (BMI=28.2+/-3.2 vs 27.1+/-2.8 kg/m(2); waist circumference (WC)=86.7+/-9.3 vs 82.5+/-8.3 cm; P<0.01). There were more subjects with impaired glucose tolerance (IGT) in group R than in group S (29.7 vs 16.0%; P<0.01). After adjustment for age and indices of global and regional obesity (ie BMI and WC), insulin-resistant individuals showed higher apolipoprotein B, triglyceride, fasting (FPG) and 2 h post-load plasma glucose (2hPG) but lower HDL and LDL size. Further adjustment for FPG, 2hPG and level of physical activity had minimal impact on the results. Insulin-resistant overweight/obese non-diabetic Asian adults had greater burden of the cardiovascular dysmetabolic syndrome than insulin-sensitive overweight/obese individuals. This could not be fully explained by differences in global and regional obesity, glucose tolerance and level of physical activity.

The somatotropic axis in short children born small for gestational age: relation to insulin resistance.

To determine whether hyperinsulinemia and reduced insulin sensitivity in individuals born small for gestational age (SGA) could be related to persisting abnormalities of the GH/IGF-I axis, we assessed overnight GH secretory profiles and measured fasting glucose, insulin, intact and 32,33 split proinsulin, and IGF-I levels in 16 short SGA children (age range 2.3-8.0 y) and in controls. Insulin sensitivity was calculated using the homeostasis model. Compared with short normal-birthweight controls (n = 7, age range 2.3-5.0 y), short SGA children had higher fasting insulin levels (means: 26.8 vs 20.6 pmol/L, p = 0.02), lower insulin sensitivity [means: 204 vs 284 %homeostasis model assessment (HOMA), p = 0.01], and higher beta cell function (112 vs 89 %HOMA, p = 0.04). SGA children also had lower levels of IGFBP-1 (87.0 vs 133.8, p = 0.04), but similar IGF-I levels (IGF-I SDS: -1.1 vs -1.7, p = 0.4). Compared with normal-height controls (n = 15, age range 5.6-12.1 y), SGA children had higher overnight GH secretion (GH maximum: 55.9 vs 39.6 mU/L, p = 0.01; mean: 13.1 vs 8.9, p = 0.004; minimum: 1.2 vs 0.6, p = 0.02). Interestingly, among SGA children, fasting insulin levels and insulin sensitivity were significantly related to overnight GH secretion (insulin sensitivity vs maximum GH: r = -0.68, p = 0.01; vs GH pulse amplitude r = -0.71, p = 0.007). The only hormone level significantly related to current height velocity was C-peptide (r = 0.75, p = 0.008). In conclusion, elevated fasting insulin levels and reduced insulin sensitivity in short SGA children was related to elevated levels of overnight GH secretion. We hypothesize that resistance to the somatotropic actions of GH and IGF-I in short SGA children may contribute directly to reduced insulin sensitivity.

Incorporation of the Fasting Plasma FFA Concentration into QUICKI Improves Its Association with Insulin Sensitivity in Nonobese Individuals

Insulin resistance plays a major role in the pathophysiology of diabetes and is associated with obesity and cardiovascular disease. Excellent methods exist for the assessment of insulin sensitivity in the laboratory setting, such as the glucose clamp. However, these methods are not suitable for large population studies, and, thus, surrogate estimates of insulin sensitivity based on measurements in a single blood sample have been developed. Recently an index based on the logarithm and the reciprocal of the insulin-glucose product (QUICKI) has been proposed. QUICKI correlated with insulin sensitivity across the entire spectrum of glucose tolerance, but its performance was less satisfactory in normal subjects. Aim of this study was to ascertain whether the inclusion of fasting plasma free fatty acids concentration into QUICKI improves its association with insulin sensitivity in nonobese subjects. To test this hypothesis, we performed a euglycemic hyperinsulinemic clamp [40 mU/(m2·min)] in 57 young, healthy, nonobese individuals with (n = 17) or without (n = 40) first-degree relatives affected by type 2 diabetes (the former group being an in vivo model of mild insulin resistance). We then compared the clamp-based index of insulin sensitivity with both QUICKI and a revised QUICKI, the latter index including the contribution of fasting free fatty acid concentration as well. The revised QUICKI considerably improved the relationship with the clamp-based index of insulin sensitivity (r = 0.51, P < 0.0001) with respect to QUICKI (r = 0.27, P < 0.05). In addition, the revised QUICKI revealed a reduction of insulin sensitivity in the offspring of type 2 diabetes (10%; P < 0.006) that QUICKI was unable to detect (3%; P = 0.28). In conclusion, this study suggests that the incorporation of fasting free fatty acid level into QUICKI is useful to improve its correlation with the clamp-based index of insulin sensitivity and its discriminatory power in case of mild insulin resistance. Further investigation is needed to ascertain its applicability to patients with obesity and type 2 diabetes.

Incorporation of the fasting plasma FFA concentration into QUICKI improves its association with insulin sensitivity in nonobese individuals.

Insulin resistance plays a major role in the pathophysiology of diabetes and is associated with obesity and cardiovascular disease. Excellent methods exist for the assessment of insulin sensitivity in the laboratory setting, such as the glucose clamp. However, these methods are not suitable for large population studies, and, thus, surrogate estimates of insulin sensitivity based on measurements in a single blood sample have been developed. Recently an index based on the logarithm and the reciprocal of the insulin-glucose product (QUICKI) has been proposed. QUICKI correlated with insulin sensitivity across the entire spectrum of glucose tolerance, but its performance was less satisfactory in normal subjects. Aim of this study was to ascertain whether the inclusion of fasting plasma free fatty acids concentration into QUICKI improves its association with insulin sensitivity in nonobese subjects. To test this hypothesis, we performed a euglycemic hyperinsulinemic clamp [40 mU/(m(2).min)] in 57 young, healthy, nonobese individuals with (n = 17) or without (n = 40) first-degree relatives affected by type 2 diabetes (the former group being an in vivo model of mild insulin resistance). We then compared the clamp-based index of insulin sensitivity with both QUICKI and a revised QUICKI, the latter index including the contribution of fasting free fatty acid concentration as well. The revised QUICKI considerably improved the relationship with the clamp-based index of insulin sensitivity (r = 0.51, P < 0.0001) with respect to QUICKI (r = 0.27, P < 0.05). In addition, the revised QUICKI revealed a reduction of insulin sensitivity in the offspring of type 2 diabetes (10%; P < 0.006) that QUICKI was unable to detect (3%; P = 0.28). In conclusion, this study suggests that the incorporation of fasting free fatty acid level into QUICKI is useful to improve its correlation with the clamp-based index of insulin sensitivity and its discriminatory power in case of mild insulin resistance. Further investigation is needed to ascertain its applicability to patients with obesity and type 2 diabetes.

Short-term high-fat diet alters substrate utilization during exercise but not glucose tolerance in highly trained athletes.

We determined the effect of a high-fat diet and carbohydrate (CHO) restoration on substrate oxidation and glucose tolerance in 7 competitive ultra-endurance athletes (peak oxygen uptake [VO(2peak)] 68 +/- 1 ml x kg(-1) x min(-1); mean +/- SEM). For 6 days, subjects consumed a random order of a high-fat (69% fat; FAT-adapt) or a high-CHO (70% CHO; HCHO) diet, each followed by 1 day of a high-CHO diet. Treatments were separated by an 18-day wash out. Substrate oxidation was determined during submaximal cycling (20 min at 65% VO(2peak)) prior to and following the 6 day dietary interventions. Fat oxidation at baseline was not different between treatments (17.4 +/- 2.1 vs. 16.1 +/- 1.3 g x 20 min(-1) for FAT-adapt and HCHO, respectively) but increased 34% after 6 days of FAT-adapt (to 23.3 +/- 0.9 g x 20 min(-1), p < .05) and decreased 30% after HCHO (to 11.3 +/- 1.4 g x 20 min(-1), p < .05). Glucose tolerance, determined by the area under the plasma [glucose] versus time curve during an oral glucose tolerance (OGTT) test, was similar at baseline (545 +/- 21 vs. 520 +/- 28 mmol x L(-1) x 90 min(-1)), after 5-d of dietary intervention (563 +/- 26 vs. 520 +/-18 mmol x L(-1) x 90 min(-1)) and after 1 d of high-CHO (491 +/- 28 vs. 489 +/- 22 mmol x L(-1) x 90 min(-1) for FAT- adapt and HCHO, respectively). An index of whole-body insulin sensitivity ( S(I), 10000/divided by fasting [glucose] x fasting [insulin] x mean [glucose] during OGTT x mean [insulin] during OGTT) was similar at baseline (15 +/- 2 vs. 17 +/- 5 arbitrary units), after 5-d of dietary intervention (15 +/- 2 vs. 15 +/- 2) and after 24 h of CHO loading (17 +/- 3 vs. 18 +/- 2 for FAT- adapt and HCHO, respectively). We conclude that despite marked changes in the pattern of substrate oxidation during submaximal exercise, short-term adaptation to a high-fat diet does not alter whole-body glucose tolerance or an index of insulin sensitivity in highly-trained individuals.

Relationship between muscle fibre composition, glucose transporter protein 4 and exercise training: possible consequences in non-insulin-dependent diabetes mellitus.

Skeletal muscle is composed of different fibre types, which differ in contractile as well as in metabolic properties. The myosin molecule, which exists in several different isoforms, is of major importance in determining the contractile properties of the muscle cell. The plasticity of skeletal muscle is reflected in this tissue's adaptability to changes in the functional demand. In both rats and humans, a decrease in activity level will in most cases change the muscle fibre composition towards faster myosin isoforms and an increase in activity level (such as seen with exercise training) will induce an increase in slower myosin isoforms. The glucose transporter protein 4 (GLUT4), which is the major insulin regulatable glucose transporter in mammalian skeletal muscle, is found in larger amounts in slow muscle fibres compared with fast muscle fibres. An increase in activity level will increase the GLUT4 protein expression and a decrease in activity level will in most cases decrease GLUT4. Thus, there seems to be some kind of relationship between the muscle fibre type and GLUT4. However, the main factor regulating both the GLUT4 protein expression and the muscle fibre composition seems to be the activity level of the muscle fibre. Patients suffering from non-insulin-dependent diabetes mellitus (NIDDM) are insulin resistant in their skeletal muscles but are generally normal when it comes to skeletal muscle fibre composition and the GLUT4 protein expression. There is good evidence that exercise training beneficially impacts on insulin sensitivity in healthy individuals and in patients with type II diabetes. An increase in the GLUT4 protein expression in skeletal muscle may at least partly explain this effect of training.

Interactions between insulin resistance and insulin secretion in the development of glucose intolerance

Subjects who develop type 2 diabetes have a complex phenotype with defects in insulin secretion, increased hepatic glucose production, and resistance to the action of insulin, all of which contribute to the development of overt hyperglycemia. Although the precise mechanisms whereby these three factors interact to produce glucose intolerance and diabetes are uncertain, it has been suggested that the final common pathway responsible for the development of type 2 diabetes is the failure of the pancreatic β cell to compensate for insulin resistance (1). Here, we review evidence for this model from both human and animal studies, and we consider the effects of specific drug treatments and of heightened FFA levels on insulin sensitivity and insulin secretion in individuals at risk for type 2 diabetes. Coleman and coworkers (2), drawing on their work with the ob/ob mouse, first proposed that a failure of β-cell compensation for insulin resistance is responsible for the development of type 2 diabetes. When insulin-resistant ob/ob mice, which provide a genetic model of obesity, were bred with mice of different strains, the phenotypes of the progeny differed depending on their genetic background. Mice carrying the ob mutation in the C57BL/6 background had relatively normal blood glucose levels, whereas in the C57Ks background the animals developed overt hyperglycemia. The major difference between these two mouse strains lay in their β-cell responses. The nondiabetic C57BL/6 mice underwent a marked expansion of β-cell mass, whereas C57Ks animals showed histologic evidence of islet degeneration, degranulation, and progressive atrophy. The C57Ks animals accordingly had insulin levels about one-tenth those of the C57BL/6 animals, and these levels declined progressively with age. These data indicated that the genetic background on which insulin resistance develops influences the adequacy of pancreatic β-cell compensation for insulin resistance, and hence the predisposition to diabetes.

Serum leptin concentrations in young insulin-sensitive and insulin-resistant volunteers.

The aim of this study was to compare metabolic profiles and serum leptin concentrations between young insulin-sensitive and insulin-resistant subjects. A cross-sectional study was performed in 32 healthy, non-obese, young volunteers. Assessing of insulin sensitivity, serum leptin concentration, serum uric acid, creatinine levels and lipid profile were done on all subjects. An insulin suppression test modified with octreotide was performed to assess insulin sensitivity. Steady state glucose (SSG) and steady state insulin concentrations were calculated. Based on the SSG data, the volunteers were divided into four quartiles, considering as insulin-sensitive individuals those from quartile 1 to quartile 3, and insulin-resistant subjects those in quartile 4. Characteristics of both groups were compared, including metabolic profile and leptin levels. After dividing SSG into quartiles, 24 subjects were considered as insulin-sensitive individuals, and 8 were assessed as insulin-resistant subjects. Total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly higher in the insulin-resistant group than in the insulin-sensitive group. Serum leptin concentration was significantly higher (p=0.05) in insulin-resistant women (6.1 +/- 3.1 ng/ml) than those considered as insulin-sensitive (3.7 +/- 2.3 ng/ml). In conclusion, insulin-resistant subjects had higher concentrations of total cholesterol and LDL-cholesterol compared to insulin-sensitive individuals. Serum leptin level was higher in insulin-resistant women than those considered as insulin-sensitive.

Association between birth weight and insulin sensitivity in healthy young men in Korea: role of visceral adiposity

Recent studies have demonstrated decreased insulin sensitivity in individuals with low birth weight. This study was performed to examine whether abdominal obesity is a link between insulin resistance and low birth weight. We studied the relationships between birth weight and insulin secretion, insulin sensitivity, and various anthropometric indices including visceral fat area in 22 healthy young Korean adults. Birth weight correlated significantly with diastolic blood pressure ( r=−0.47, P<0.05) and insulin sensitivity index ( S I) measured by a frequently sampled intravenous glucose tolerance test (FSIGT) ( r=0.54, P<0.05), but not with insulin secretory indices such as acute insulin responses during FSIGT ( r=−0.35, NS) or hyperglycemic clamp ( r=0.17, NS) and submaximum insulin response during hyperglycemic clamp ( r=0.10, NS). S I correlated significantly with abdominal obesity measurements such as waist circumference ( r=−0.48, P<0.05), waist-to-hip ratio ( r=−0.53, P<0.05) and visceral fat area ( r=−0.58, P<0.01). However, we could not find significant correlation between birth weight and any of the abdominal obesity measurements ( r=−0.35 for waist-to-hip ratio, r=−0.22 for visceral fat area, and r=−0.24 for visceral-to-subcutaneous fat ratio; NS for all). The present data confirm that low birth weight is associated with insulin resistance in adult life. However, our data suggest that the association between low birth weight and insulin resistance is not mediated by abdominal obesity.

Insulin sensitivity and fertility

This review sets in context significant recent advances in the understanding of the pathophysiology of polycystic ovary syndrome (PCOS). The occurrence of variable insulin sensitivity in individuals is discussed. Information is presented to demonstrate that prolonged anovulation decreases insulin sensitivity and, conversely, that improvement in insulin sensitivity normalizes ovarian function in PCOS. In addition, a meta-analysis of studies on metformin and troglitazone treatment in PCOS is presented.

Loss of the normal coupling between the anaerobic threshold and insulin sensitivity in chronic heart failure

OBJECTIVETo explore whether the anaerobic threshold, a measure of the balance between aerobic and anaerobic cellular metabolism, is related to whole body insulin sensitivity in healthy individuals and in patients...

Insulin resistance versus impaired insulin secretion as the genetic basis for type 2 diabetes

The relative roles of impaired insulin secretion and insulin resistance in the pathogenesis of type 2 diabetes continue to be controversial. The controversy centers on two issues: the most important genetic factor in type 2 diabetes and the most important factor determining the magnitude of hyperglycemia. This review attempts to determine the most important genetic factor. It is widely believed that insulin resistance is the primary genetic factor in type 2 diabetes. The original bases for this belief have come under question, however, and recent studies using sophisticated methods (eg, glucose clamps, minimal modeling) to assess insulin secretion and insulin sensitivity in certain well-characterized individuals have tended to support the view that impaired insulin secretion is the primary genetic factor in type 2 diabetes.

Clinical Aspects of Leptin

Hyperleptinemia is an essential feature of human obesity. Total body fat mass > % body fat > BMI are the best predictors of circulating leptin levels. Although ob gene is differentially expressed in different fat compartments, apart from total body fat, upper or lower body adiposity or visceral fat does not influence basal leptin levels. Similarly, age, basal glucose levels, and ethnicity do not influence circulating leptin levels. Only in insulin-sensitive individuals do basal levels of insulin and leptin correlate positively even after factoring in body fat. Diabetes does not influence leptin secretion in both lean and obese subjects per se. Independent of adiposity, leptin levels are higher in women than in men. This sexual dimorphism is also present in adolescent children. In eating disorders anorexia nervosa and bulimea nervosa, leptin levels are not upregulated but simply reflect BMI and probably body fat. In spite of strong correlation between body fat and leptin levels, there is great heterogeneity in leptin levels at any given index of body fat. About 5% of obese populations can be regarded as "relatively" leptin deficient which could benefit from leptin therapy. Leptin has dual regulation in human physiology. During the periods of weight maintenance, when energy intake and energy output are equal, leptin levels reflect total bodyfat mass. However, in conditions of negative (weight-loss programs) and positive (weight-gain programs) energy balances, the changes in leptin levels function as a sensor of energy imbalance. This latter phenomenon is best illustrated by short-term fasting and overfeeding experiments. Within 24 h of fasting leptin levels decline to approximately 30% of initial basal values. Massive overfeeding over a 12-h period increases leptin levels by approximately 50% of initial basal values. Meal ingestion does not acutely regulate serum leptin levels. A few studies have shown a modest increase in leptin secretion at supraphysiological insulin concentrations 4-6 h following insulin infusion. Under in vitro conditions, insulin stimulates leptin production only after four days in primary cultures of human adipocytes, which is apparently due to its trophic effects and an increased fat-cell size. Similar to other hormones, leptin secretion shows circadian rhythm and oscillatory pattern. The nocturnal rise of leptin secretion is entrained to mealtime probably due to cumulative hyperinsulinemia of the entire day. Like other growth factors and cytokines, leptin binding proteins including soluble leptin receptor are present in human serum. In lean subjects, the majority of leptin circulates in the bound form whereas in obese subjects, the majority of leptin is present in the free form. When free-leptin levels are compared between lean and obese subjects, even more pronounced hyperleptinemia in obesity is observed than that reported by measuring total leptin levels. During short-term fasting, free-leptin levels in lean subjects decrease in much greater proportion than those in obese subjects. In lean subjects with a relatively small energy store and particularly during food deprivation, leptin circulating predominantly in the bound form could be the mechanism to restrict its availability to hypothalamic leptin receptors for inhibiting leptin's effect on food intake and/or energy metabolism. Unlike marked changes in serum leptin, CSF leptin is only modestly increased in obese subjects and the CSF leptin/serum leptin ratio decreases logarithmically with increasing BMI. If CSF leptin levels are any indication of brain interstitial fluid levels, then hypothalami of obese subjects are not exposed to abnormally elevated leptin concentrations. In the presence of normal leptin receptor (functional long form, i.e., OB-Rb) mRNA expression and in the absence of leptin receptor gene mutations, it is logical to assume defective leptin signaling and/or impaired affector system(s) are the likely causes of leptin resistance in

Insulin resistance does not change the ratio of proinsulin to insulin in normal volunteers.

Plasma glucose, insulin, and proinsulin concentrations were measured before and after an oral glucose challenge in 57 nondiabetic individuals. In addition, insulin-mediated glucose disposal was estimated by determining the steady state plasma glucose (SSPG) concentration after a 180-min iv infusion of somatostatin, insulin, and glucose. The plasma glucose concentration after oral glucose administration was used to divide the population into those with normal (n = 36) or impaired glucose tolerance (IGT; n = 21), and the 36 normal glucose-tolerant individuals were further subdivided into an insulin-sensitive (SSPG, < 9.0 mmol/L; n = 15) and an insulin-resistant (SSPG, > 10 mmol/L; n = 21) group. Fasting and postglucose load insulin concentrations were similar in the normal glucose-tolerant insulin-resistant and IGT groups, but were significantly higher (P < 0.02- < 0.001) than those in normal glucose-tolerant insulin-sensitive individuals. Fasting proinsulin concentrations were also higher (P < 0.002) in the normal glucose-tolerant insulin-resistant (15.1 +/- 1.5 pmol/L) and IGT (15.8 +/- 1.8 pmol/L) groups compared to those in normal glucose-tolerant insulin-sensitive volunteers (9.3 +/- 1.2 pmol/ L). However, the ratio of fasting proinsulin to insulin was identical in all three groups (0.12). When the three groups were combined, significant relationships (P < 0.001) existed between SSPG (degree of insulin resistance) and both fasting proinsulin (r = 0.59) and insulin (r = 0.66) concentrations, but not with the ratio of proinsulin to insulin (r = 0.03). These results demonstrate that fasting proinsulin and insulin concentrations are increased in insulin-resistant, nondiabetic subjects, and the more insulin resistant, the greater the increase. In contrast, the ratio of proinsulin to insulin did not vary as a function of insulin resistance. Thus, neither insulin resistance nor the need to secrete more insulin to maintain glucose tolerance necessarily leads to abnormal insulin processing by the beta-cell.