Non-obese Diabetics Research Articles

Reduction in Aerobic Capacity and Cardiac Output in Diabetic Adolescents

Aerobic capacity is reduced in diabetic adults. Type 1 diabetic (T1D) adolescents also have reduced aerobic capacity; however it is not known whether recently diagnosed type 2 diabetic (T2D) adolescents have similarly impaired aerobic capacity. PURPOSE: To determine whether T2D and T1D adolescents have reduced aerobic capacity and whether stroke volume (SV) and heart rate (HR) response to exercise are impaired in diabetic adolescents. METHODS: Eight T2D, 10 non-diabetic obese (NDO), 11 T1D and 7 lean (L) female adolescents were recruited for this study. Baseline data included peak aerobic capacity (cycle ergometer) and a DEXA scan. On a separate day, cardiac output (CO) was determined at rest and during workloads eliciting 100(±5)and 120 (±5) beats per minute (bpm). RESUITS: Maximal O2 consumption (ml/kgFFM/min) and HR (bpm) were lower in the T2D vs. NDO, T1D and L groups (p< 0.05). Resting CO and SV indexed for fat free mass (COFFM and SVFFM) were lower in both diabetic and NDO groups compared to L group (p< 0.05). Exercise COFFM and SVFFM were lower during both workloads in the T1D and T2D vs. NDO and L groups (p< 0.05). Arterio-venous O2 difference was not different in any condition (p> 0.05). CONCLUSION: T2D adolescents have lower aerobic capacity than T1D and NDO adolescents even when indexed to fat free mass. However both T1D and newly diagnosed T2D adolescents have blunted stroke volume response to exercise.TableData are means ± standard deviation. B= p< 0.05 significantly ≠ between T2D and O, C= p< 0.05 significantly ≠ between T2D and L, D= p< 0.05 significantly ≠ between O and T1D, E= p< 0.05 significantly ≠ between O and L, F= p< 0.05 significantly ≠ between T1D and L.

Autonomic Neuropathy Increases the Risk of Obstructive Sleep Apnea in Obese Diabetics

Background: Nonobese diabetics with diabetic autonomic neuropathy (DAN) show an elevated prevalence of obstructive sleep apnea-hypopnea (OSAH). Objective: It was the aim of this study to assess if the presence of DAN could further increase the risk of developing OSAH in obese diabetics. Methods: Eighteen obese diabetic patients, 8 with DAN [age 57 ± 5 years, body mass index (BMI) 35 ± 4] and 10 without DAN (age 56 ± 8 years, BMI 37 ± 5), were recruited. Ten age-matched obese subjects were studied as controls (age 53 ± 12 years, BMI 34 ± 3). All subjects underwent a cardiorespiratory sleep study in the in-hospital sleep laboratory to obtain the apnea-hypopnea index (AHI) and oxygen desaturation indices. Results: Diabetics with DAN (Ob-DAN+) had a higher AHI than diabetics without DAN (Ob-DAN–) and controls, amounting to 39.5 ± 13 versus 15.8 ± 12 (p < 0.01) and 19.3 ± 21 (p < 0.05), respectively. A moderate-to-severe OSAH (AHI ≧15) occurred in all Ob-DAN+ and only in 4 Ob-DAN– and 4 control patients. Moreover, the indices reflecting the impairment of oxygen saturation (SaO₂) during sleep such as the mean lowest SaO₂ and sleep time with a SaO₂ <90% were more severely affected in Ob-DAN+ patients compared with the other groups and were associated with longer obstructive respiratory events. Conclusions: Apneas-hypopneas are more frequent and last longer in Ob-DAN+ than in other obese subjects, with or without diabetes.

Salsalate May Improve Metabolic Outlook in Obese Nondiabetics

Salsalate May Improve Metabolic Outlook in Obese Nondiabetics

Comparison of Body Fat Composition and Serum Adiponectin Levels in Diabetic Obesity and Non‐diabetic Obesity

Clinical aspects of diabetes and obesity are somewhat different, even at similar levels of insulin resistance. The purpose of this study was to determine differences in body fat distribution and serum adiponectin concentrations in diabetic and non-diabetic obese participants. We were also interested in identifying the characteristics of insulin resistance in these two groups, particularly from the standpoint of adiponectin. Adiponectin concentrations of 112 type 2 diabetic obese participants and 124 non-diabetic obese participants were determined. Abdominal adipose tissue areas and midthigh skeletal muscle areas were measured by computed tomography. A homeostasis model assessment of the insulin resistance score was calculated to assess insulin sensitivity. The relationships among serum adiponectin, body fat distribution, and clinical characteristics were also analyzed. Both abdominal subcutaneous and visceral fat areas were higher in the non-diabetic obese group, whereas midthigh low-density muscle area was higher in the diabetic obese group. The homeostasis model assessment of the insulin resistance score was similar between groups, whereas serum adiponectin was lower in the diabetic obese group. Abdominal visceral fat (beta = -0.381, p = 0.012) was a more important predictor of adiponectin concentration than low-density muscle (beta = -0.218, p = 0.026) in cases of non-diabetic obesity, whereas low-density muscle (beta = -0.413, p = 0.013) was a better predictor of adiponectin level than abdominal visceral fat (beta = - 0.228, p = 0.044) in diabetic obese patients. Therefore, factors involved in pathophysiology, including different serum adiponectin levels and body fat distributions, are believed to be responsible for differences in clinical characteristics, even at similar levels of insulin resistance in both diseases.

Intra-abdominal Fat Adiponectin Receptors Expression and Cardiovascular Metabolic Risk Factors in Obesity and Diabetes

The effects of adiponectin on glucose and lipid metabolism are mediated by the adiponectin receptors, adipoR1 and adipoR2, which are mainly in liver and muscle. We investigated the presence of adiponectin receptors in intra-abdominal adipose tissue (IAAT) in obesity and diabetes and their association with adiponectin expression and components of the metabolic syndrome and/or other metabolic factors associated with atherosclerotic cardiovascular disease (ASCVD). AdipoR1 and adipoR2 gene expression was measured by quantitative real time reverse transcription polymerase chain reaction in IAAT from lean and obese patients with or without diabetes type 2. Correlation between metabolic characteristics of obese patients and expression of these receptors was studied. Neither obesity nor diabetes were associated with changes in IAAT-adipoR1 expression. In contrast, IAAT-adipoR2 was decreased by 39.5% in obese non-diabetics and by 52.7% in obese diabetics when compared to lean subjects. AdipoR1 and adiponectin expression was associated in lean (r=0.943, P<0.005) and obese non-diabetic patients (r=0.74, P<0.01), whereas a positive correlation between adipoR2 and adiponectin expression was only found in the presence of diabetes (r=0.883, P<0.002). AdipoR1 expression was associated with plasma free fatty acids (FFA) concentration (r=0.76, P<0.04), and adipoR2 inversely correlated with plasma levels of triglycerides (r=-0.76, P<0.04) and apolipoprotein B (r=-0.74, P<0.05). AdipoR1 expression in IAAT was not altered by obesity and/or diabetes and was related to plasma levels of FFA. IAAT-adipoR2 expression was reduced in obesity and diabetes and associated with components of metabolic processes leading to cardiovascular disease in obesity.

Increased collagen content in insulin-resistant skeletal muscle

Oversupply and underutilization of lipid fuels are widely recognized to be strongly associated with insulin resistance in skeletal muscle. Recent attention has focused on the mechanisms underlying this effect, and defects in mitochondrial function have emerged as a potential player in this scheme. Because evidence indicates that lipid oversupply can produce abnormalities in extracellular matrix composition and matrix changes can affect the function of mitochondria, the present study was undertaken to determine whether muscle from insulin-resistant, nondiabetic obese subjects and patients with type 2 diabetes mellitus had increased collagen content. Compared with lean control subjects, obese and type 2 diabetic subjects had reduced muscle glucose uptake (P<0.01) and decreased insulin stimulation of tyrosine phosphorylation of insulin receptor substrate-1 and its ability to associate with phosphatidylinositol 3-kinase (P<0.01 and P<.05). Because it was assayed by total hydroxyproline content, collagen abundance was increased in muscle from not only type 2 diabetic patients but also nondiabetic obese subjects (0.26+/-0.05, 0.57+/-0.18, and 0.67+/- 0.20 microg/mg muscle wet wt, lean controls, obese nondiabetics, and type 2 diabetics, respectively), indicating that hyperglycemia itself could not be responsible for this effect. Immunofluorescence staining of muscle biopsies indicated that there was increased abundance of types I and III collagen. We conclude that changes in the composition of the extracellular matrix are a general characteristic of insulin-resistant muscle.

Independent effect and population impact of obesity on fatal coronary heart disease in adults

Background. It is unclear whether the coronary heart disease (CHD) mortality risk associated with obesity is mediated only through traditional CHD risk factors. This analysis evaluated the independent CHD mortality risk due to obesity and determined its population attributable risk (PAR). Methods. Using the NHANES I Epidemiologic Follow-up Study (1971–1992, n = 10,582), a diabetes-body mass index (BMI) variable was constructed. The hazard ratios (HR) for fatal CHD in the diabetes-BMI categories (adjusting for age, sex, race, exercise, education level, smoking, hypertension, cholesterol, and alcohol use) were determined and the PARs subsequently estimated. Results. Compared to lean non-diabetics, the HR (95% CI) for fatal CHD is 0.8 (0.7, 1.1) in overweight non-diabetics, 1.4 (1.3, 2.0) in obese non-diabetics, 2.2 (1.2, 4.0) in lean diabetics, 2.3 (1.4, 3.9) in overweight diabetics, and 3.3 (1.9, 8.9) in obese diabetics. The PAR% is −6.8 (−15.7, 1.8) in overweight non-diabetics, 6.1 (1.7, 11.1) in obese non-diabetics, 2.0 (0.3, 4.0) in lean diabetics, 2.2 (0.6, 4.3) in overweight diabetics, and 2.2 (0.8, 3.8) in obese diabetics. Conclusions. Obesity is an independent risk factor for CHD mortality even after controlling for traditional CHD risk factors. The PAR for CHD death in obese non-diabetics is significant. Obesity should be aggressively treated in those without traditional CHD risk factors.

Adipocyte Differentiation‐related Protein in Human Skeletal Muscle: Relationship to Insulin Sensitivity

To determine whether adipocyte differentiation-related protein (ADRP), a lipid droplet-associated protein that binds to and sequesters intracellular fatty acids, is 1) expressed in human skeletal muscle and 2) differentially regulated in human skeletal muscle obtained from obese non-diabetic (OND) and obese diabetic (OD) subjects. Ten OND subjects and 15 OD subjects underwent a weight loss or pharmacological intervention program to improve insulin sensitivity. Anthropometric data, hemoglobin A(1C), fasting glucose, lipids, and glucose disposal rate were determined at baseline and at completion of studies. Biopsies of the vastus lateralis muscle (SkM) were obtained in the fasting state from OND and OD subjects. Protein expression was determined by Western blotting. ADRP was highly expressed in SkM from OND (4.4 +/- 1.54 AU/10 microg, protein, n = 10) and OD (5.02 +/- 1.33 AU/10 microg, n = 12) subjects. OND subjects undergoing weight loss had decreased triglyceride levels and improved insulin action. SkM ADRP content increased with weight loss from 5.14 +/- 2.15 AU/10 microg to 9.92 +/- 1.57 AU/10 microg (p < 0.025). OD subjects were treated with either troglitazone or metformin, together with glyburide, for 3 to 4 months. Both treatments attained similar levels of glycemic control. OD subjects with lower baseline ADRP content (2.85 +/- 1.07 AU/10 microg, n = 6) displayed up-regulation of ADRP expression (to 9.27 +/- 2.76 AU/10 microg, p < 0.025). ADRP is the predominant lipid droplet-associated protein in SkM, and low ADRP expression is up-regulated in circumstances of improved glucose tolerance. Up-regulation of ADRP may act to sequester fatty acids as triglycerides in discrete lipid droplets that could protect muscle from the detrimental effects of fatty acids on insulin action and glucose tolerance.

Prevalence of Left Ventricular Diastolic Dysfunction in Obese Persons With and Without Diabetes Mellitus

Forty obese diabetic patients (mean age 48 +/- 9 years) and 93 obese nondiabetic patients (mean age 43 +/- 9 years) underwent Doppler and tissue Doppler echocardiographic evaluation of left ventricular diastolic function before gastric bypass surgery. Moderate or severe left ventricular diastolic dysfunction was present in 24 of 40 obese diabetics (60%) and in 21 of 93 obese nondiabetics (23%) (p <0.001).

Skeletal muscle GLUT1 transporter protein expression and basal leg glucose uptake are reduced in type 2 diabetes.

To investigate the role of skeletal muscle tissue expression of the glucose transporter protein GLUT1 in mediating glucose disposal in the basal (fasting) state, skeletal muscle biopsies (vastus lateralis) were obtained from lean and obese nondiabetics and type 2 diabetic subjects. Basal and insulin-stimulated glucose uptakes were measured. Basal whole body glucose uptake was measured using isotope dilution, and arteriovenous catheterization limb balance was used to determine leg muscle glucose uptake. Basal (noninsulin-stimulated) whole body glucose uptake was higher in the type 2 group compared with the controls (2.26 +/- 0.17 vs. 1.83 +/- 0.15 mg/kg.min; P < 0.05). However, basal leg muscle glucose uptake was reduced in diabetic subjects (1.53 +/- 0.56 vs. 3.89 +/- 0.83 mg/100 ml.min; P < 0.025) despite basal hyperglycemia (230 +/- 13 vs. 94 +/- 2 mg/dl; P < 0.0005). Skeletal muscle GLUT1 protein expression was lower in the type 2 subjects (57 +/- 12 vs. 91 +/- 11 arbitrary units/10 microg protein; P < 0.05), although GLUT1 mRNA levels did not differ. In summary, 1) skeletal muscle tissue GLUT1 protein expression is reduced in type 2 diabetes and could contribute to impaired basal leg glucose uptake; and 2) elevated rates of basal whole body glucose uptake in type 2 diabetes are due to uptake in tissues other than skeletal muscle.

"Low Dose" Metformin Improves Hyperglycemia Better Than Acarbose in Type 2 Diabetics

"High dose" metformin therapy (2,550 mg/day) is reported to improve glycemic control in type 2 diabetic patients with obesity (body mass index (BMI) > or = 30). Some have reported that metformin therapy, even in low doses (500-750 mg/day), improves glycemic control in non-obese type 2 diabetic patients (BMI approximately 25). However, it is unclear whether "low dose" metformin improves glycemic control better than acarbose in non-obese type 2 diabetic patients, which has been shown to improve glycemic control in type 2 diabetes with obesity. We randomly divided 22 non-obese type 2 diabetic patients (mean BMI approximately 25) into two groups (A = 11, B = 11). Group A was treated with "low dose" metformin (500-750 mg/day) for 3 months, and switched to acarbose (150-300 mg/day) for another 3 months. Group B was treated with acarbose first, and then switched to "low dose" metformin. "Low dose" metformin significantly decreased the fasting plasma glucose (FPG) and HbA1c level in both groups A and B, whereas acarbose decreased HbA1c levels in group B but not in group A. Overall, "low dose" metformin significantly decreased HbA1c (p=0.0165) levels as compared to acarbose. In conclusion, "low dose" metformin therapy improved glycemic control better than acarbose in non-obese diabetics.

Sleep-disordered breathing in nonobese diabetic subjects with autonomic neuropathy

To assess the occurrence and nature of sleep-disordered breathing (SDB) in 26 adult, nonobese diabetics (18 with autonomic neuropathy (DAN+) (age 45 (41-50) yrs; body mass index (BMI) 24.1 (22-26) kg x m(-2)) and eight without autonomic neuropathy (DAN-) (age 45 (35-55) yrs; BMI 24.8 (23-26) kg x m(-2))) overnight full sleep studies and measurements of central and peripheral carbon dioxide (CO2) chemosensitivity were performed. DAN+ were divided in two subgroups, according to the presence (DAN+PH+; n=10) or absence (DAN+PH-; n=8) of postural hypotension. Ten normal subjects were studied as controls (age 42 (36-48) yrs; BMI 24.4 (23-25) kg x m(-2)). In contrast to DAN- and controls, who did not show SDB, five DAN+ (four DAN+PH- and one DAN+PH+) had an apnoea/hypopnoea index > or = 10 and four DAN+ (two DAN+PH- and two DAN+PH+) had an apnoea index > or = 5. All the events were obstructive, occurring mainly during rapid eye movement (REM) sleep. Ten DAN+ exhibited a mean lowest oxygen saturation < 90% during REM sleep. No periodic breathing or central sleep apnoeas were found in DAN+PH+, although they had an enhanced central chemoresponsiveness to CO2. Both DAN+ subgroups showed a marked reduction in peripheral CO2 chemosensitivity. In conclusion, adult nonobese diabetics with autonomic neuropathy, independent of the severity of their dysautonomy, have obstructive sleep apnoea/hypopnoea with a frequency > 30%. A decrease in peripheral carbon dioxide chemosensitivity prevents adult nonobese diabetics with autonomic neuropathy and postural hypotension from experiencing posthyperventilatory central sleep apnoea, despite an increased hypercapnic central drive.

Localization of a Susceptibility Gene for Type 2 Diabetes to Chromosome 5q34–q35.2

We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 2.90, P=1.29 x 10(-4)) in all diabetics. Since obesity, here defined as body mass index (BMI) > or =30 kg/m(2), is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI > or =30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 3.64, P=2.12 x (10)-5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12 x 10(-5)) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.

Fasting and daylong triglycerides in obesity with and without type 2 diabetes

Postprandial hypertriglyceridemia associated with insulin resistance is one of the cardiovascular risk factors in obesity and type 2 diabetes. It is not known whether diabetics have a more pronounced postprandial hypertriglyceridemia than obese subjects. Daylong triglyceridemia, representing postprandial lipemia, was determined in obese subjects with and without type 2 diabetes and in lean subjects. Nineteen type 2 diabetics (F/M: 7/12, body mass index [BMI]: 30.6 ± 5.4 kg/m 2), 45 obese nondiabetics (F/M: 16/29, BMI: 29.5 ± 2.6 kg/m 2) and 78 lean subjects (F/M: 28/50, BMI: 23.7 ± 2.2 kg/m 2) measured capillary triglycerides (TGc) during 3 days on 6 fixed time-points each day in an out-of-hospital situation. Daylong TGc profiles were calculated as mean integrated area under the TGc-curve (TGc-AUC). Fasting plasma TG were higher in diabetics and obese nondiabetics (1.81 ± 0.79 and 1.77 ± 0.80 mmol/L) compared with lean subjects (1.23 ± 0.67 mmol/L, P < .001). TGc-AUC was similarly increased in both diabetics and obese nondiabetics (35.0 ± 12.1 and 35.2 ± 10.6 mmol ·1 h/L) compared with lean controls (25.5 ± 12.0 mmol ·1 h/L, P < .001). Self-reported energy intake was not significantly different between the groups. Fasting TGc ( r = .87, P < .001) and waist circumference ( r = .51, P < .001) were the parameters best associated with TGc-AUC. Using stepwise multiple regression analysis, fasting TGc, BMI, total cholesterol, and high-density lipoprotein (HDL) cholesterol were the best predictors of TGc-AUC, explaining 77% of the variation. The cut-off level for “normal” TGc-AUC, calculated as the 75th percentile of TGc-AUC in lean subjects, was 30.7 mmol ·1 h/L and corresponded with a fasting TGc of 1.8 mmol/L (eg, 1.6 mmol/L in plasma), calculated using univariate regression analysis. In conclusion, daylong triglyceridemia is similarly increased in diabetics and obese nondiabetics compared with lean subjects. Fasting TG and central obesity largely determine daylong triglyceridemia, independent of the presence of type 2 diabetes. Decreasing fasting plasma TG below 1.6 mmol/L could lead to a normalization of postprandial lipemia in obese subjects with and without diabetes.

Detection of insulin resistance in Turkish adults: a hospital‐based study

The aim of the present study was to investigate the usefulness of insulin sensitivity check indices in our hospital population. Both HOMA (insulin X glucose in mmol/l/22.5) and QUICKI (1/log insulin in microu/ml + log glucose in mg/dl) indices were calculated from fasting values in 1,774 subjects from the medical records of Baskent University Adana Hospital. Subjects with diabetes, hyperlipidaemia and central obesity were characterized by significantly higher HOMA and lower QUICKI indices than those of healthy subjects. A fall in the QUICKI index (0.3469 +/- 0.028 in healthy subjects and 0.3247 +/- 0.025 in non-obese diabetics) as well as an increase in HOMA index (2.24 +/- 1.26 in healthy subjects and 3.59 +/- 2.08 in non-obese diabetics) corresponded to metabolic and clinical manifestations of insulin resistance in various groups of subjects. Age, low HDL cholesterol, male sex, type 2 DM and hypertension were independent risk factors for CAD. Age, male sex, waist circumference and CAD were found to be risk factors for hypertension. Fasting insulin and glucose levels contain sufficient information to assess insulin sensitivity over a wide range in a diverse population. The following can be accepted as mean values to assess insulin resistance in our hospital population: 0.3469 +/- 0.028 for the QUICKI index and 2.24 +/- 1.26 for the HOMA index HOMA and QUICKI indices are simple and reproducible methods for determining insulin sensitivity in humans.

Systemic and regional free fatty acid metabolism in type 2 diabetes

To determine whether type 2 diabetes mellitus alters systemic and regional free fatty acid ([3H]palmitate) metabolism, 14 nondiabetic (ND) and 14 type 2 diabetic (D) subjects underwent hyperinsulinemic-hyperglycemic (approximately 9.3 mM) clamps. The subjects were matched for age, body mass index, percent body fat, and fat-free mass. D subjects had more (P < 0.05) visceral fat than ND. During somatostatin, replacement growth hormone, and glucagon infusions, insulin was infused to achieve moderate (approximately 75 pmol/l) and high (approximately 150 pmol/l) physiological insulin levels. D subjects had greater (P < 0.02) systemic and regional (splanchnic and leg) palmitate release than ND subjects during both insulin infusion intervals. The relative contributions of splanchnic, leg, and nonsplanchnic upper body regions to systemic palmitate release did not differ between groups, although the last contributed the most (approximately 75%) to systemic palmitate release. Visceral fat area correlated with systemic palmitate flux (r = 0.45, P < 0.03) during both insulin infusions. We conclude that type 2 diabetes is associated with a generalized impairment in insulin suppression of lipolysis compared with equally obese ND individuals.

Leptin concentration in non-obese and obese children with type 1 diabetes mellitus

Leptin, the product of the ob gene, is an adipocyte-derived hormone that positively correlates with body fat percantage and body mass index (BMI). There are many data which demonstrate a significant relationship between leptin and insulin, but the mechanism underlying the changes of leptin induced by insulin and vice versa remains to be studied in more detail. In this review, we analysed the data on the behaviour of serum leptin levels in non-obese and obese children with type 1 diabetes mellitus. It has been shown that the diminished serum leptin concentrations in patients with newly discovered insulin-dependent diabetes mellitus (IDDM) could be caused by insulin deficiency and/or increased lipolysis. Moreover, while in some studies in diabetic children with good metabolic control the serum leptin levels are similar to those of healthy children, in other studies children with IDDM have leptin levels higher than non diabetic children; it is possible that in some diabetic children intensified insulin therapy could cause chronic hyperinsulinemia with high leptin levels. The mean serum leptin concentrations in the obese diabetic subjects were significantly higher when compared with non-obese diabetics. Obese diabetic patients showed no significant differences in leptin concentrations in comparison to the non diabetic obese group matched by age, sex and BMI. In obese diabetics, during weight loss, independent of the quality of metabolic control, serum leptin concentration declines. The changes of leptin in diabetes seem to be similar to those observed in healthy obese subjects.

Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.

The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance.

Serum complement protein C3 concentration is elevated in insulin resistance in obese men

Background. Complement protein C3 is vital to all three complement activation pathways. Chronic activation of the complement system may also have detrimental effects such as increased risk for cardiovascular disease. Previous literature suggest an association between serum C3 levels and the insulin resistance syndrome, but this has never been investigated directly. The present study was undertaken to examine directly whether C3 protein levels are associated with insulin resistance. Methods. Insulin sensitivity and fasting serum C3 levels were determined in type 2 diabetic men and age-matched obese and nonobese nondiabetic men. To differentiate between the effects of chronic hyperglycemia and obesity on insulin sensitivity, we also studied a group of type 1 diabetic men with normal body weight and matched healthy controls. Results. Fasting serum C3 levels were elevated in 10 obese nondiabetic men (body mass index (BMI) 30.5±1.0 kg/m 2, age 57±2 years, C3 1.28±0.04 g/l) as compared to nine age-matched lean nondiabetic men (BMI 23.1±0.4 kg/m 2, 59±2 years, C3 0.96±0.03 g/l, P<0.001). Serum C3 levels were similar in 12 type 2 diabetic patients (BMI 29.7±1.0 kg/m 2, age 59±2 years, C3 1.32±0.08 g/l) and in obese nondiabetic men. C3 levels correlated indirectly with glucose disposal rate in type 2 diabetic patients and in obese nondiabetics but not in lean nondiabetic men. In 23 type 1 diabetic patients (BMI 22.9±0.4 kg/m 2, age 29±1 years, C3 1.01±0.03 g/l) and 11 matched healthy men (BMI 23.7±0.7 kg/m 2, 27±2 years, C3 1.09±0.06 g/l), fasting C3 levels were similar and did not correlate with glucose disposal rate. Conclusion. Serum C3 levels are associated with insulin resistance in obesity, but not with insulin resistance induced by chronic hyperglycemia in lean type 1 diabetic patients.

Utility of metformin as an adjunct to hydroxycitrate/carnitine for reducing body fat in diabetics

Excessive exposure of tissues to fatty acids is likely to be the chief cause of the various dysfunctions that lead to sustained hyperglycemia in type II diabetes. These dysfunctions are likely to be substantially reversible if body fat and dietary fat can be greatly reduced. Disinhibition of hepatic fatty acid oxidation with hydroxycitrate (HCA) and carnitine has considerable potential as a new weight-loss strategy, but in diabetics runs the risk of further enhancing excessive hepatic gluconeogenesis. Since the clinical utility of metformin in diabetes is probably traceable to inhibition of gluconeogenesis, its use as an adjunct to HCA/carnitine treatment of obesity in diabetics deserves evaluation, particularly as metformin therapy itself tends to reduce body weight. A consideration of relevant evidence suggests that metformin therapy will not impede the activation of fatty acid oxidation by HCA/carnitine, and is likely to potentiate the appetite-suppressant and thermogenic benefits of this strategy. Indeed, since metformin has been reported to lower body weight and improve cardiovascular risk factors in obese non-diabetics, a broader application of a metformin/HCA/carnitine therapy for obesity can be contemplated.