Onset Of Impaired Glucose Tolerance Research Articles

Association of Glycosylated Hemoglobin Levels with Insulin Resistance in Adolescent among Medical Students Ain Shams University

Abstract Background Insulin resistance is a common pathway for the development of glucose metabolism disorders and high blood pressure, all of which are components of the metabolic syndrome. The earlier onset of obesity may cause a longer period of insulin resistance, which may explain the concomitant earlier onset of impaired glucose tolerance in young obese people and adolescents so insulin resistance has been implicated as risk factor for metabolic disorders and it is of real importance to develop simple test that can be used in routine clinical setting for identifying insulin resistant individuals in advance so HOMA-IR(Homeostatic Model Assessment for Insulin Resistance) and HbA1c (glycated haemoglobin) screening to identify young at high risk for insulin resistance and diabetes at an early stage. The study aimed to evaluate the association of HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) and HbA1c levels in overweight and nonoverweight young medical students to assess insulin resistance, a condition that can cause diabetes mellitus and metabolic syndrome in earlier life. Subject and Methods The study was systematic random sample was conducted between 40 overweight and 40 non-overweight students (80 in total). All cases were subjected to history taking, clinical examination and laboratory investigations included HOMA-IR and HbA1c. Results Regarding HOMA-IR in present study they illustrated statistically significant difference between groups with higher levels in overweighed group than for normal weight group.HOMA-IR ≥2.5 was represent (17.5%)of normal weight group and (45.0%) of overweighed group with statistically significant difference. N statistically significant difference regarding Glucose (mg/dl) level for normal and overweighed group. The relation was statistically significant regarding Insulin (mIU/ml) level as it was higher in overweighed group than normal group. Regarding HbA1c% in present study; there is no statistically significant difference between normal group compared to obese group that range within normal values with higher result in obese group. Our study found statistically significant association between HOMA-IR<2.5 and (glucose and insulin), in both groups and for HbA1c in obese group. Also statistically significant positive correlation between HOMA-IR and HbA1c% in all patients. Conclusion Obesity is significantly associated with higher levels of fasting insulin, and HOMA-IR values in adolescents. There is a positive correlation between HbA1c and HOMA-IR

Branched-Chain Amino Acids and Insulin Resistance, from Protein Supply to Diet-Induced Obesity.

For more than a decade, there has been a wide debate about the branched-chain amino acids (BCAA) leucine, valine, and isoleucine, with, on the one hand, the supporters of their anabolic effects and, on the other hand, those who suspect them of promoting insulin resistance. Indeed, the role of leucine in the postprandial activation of protein synthesis has been clearly established, even though supplementation studies aimed at taking advantage of this property are rather disappointing. Furthermore, there is ample evidence of an association between the elevation of their plasma concentrations and insulin resistance or the risk of developing type 2 diabetes, although there are many confounding factors, starting with the level of animal protein consumption. After a summary of their metabolism and anabolic properties, we analyze in this review the factors likely to increase the plasma concentrations of BCAAs, including insulin-resistance. After an analysis of supplementation or restriction studies in search of a direct role of BCAAs in insulin resistance, we discuss an indirect role through some of their metabolites: branched-chain keto acids, C3 and C5 acylcarnitines, and hydroxyisobutyrate. Overall, given the importance of insulin in the metabolism of these amino acids, it is very likely that small alterations in insulin sensitivity are responsible for a reduction in their catabolism long before the onset of impaired glucose tolerance.

Development of pups born to rats established as a model of underweight Japanese women and the onset of impaired glucose tolerance

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers.

From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management.

Aims Despite the very clear association between polycystic ovary syndrome (PCOS) and dysglycemia, few studies have explored the continuum of glycemic alterations leading from minor glucose abnormalities to overt diabetes. The purpose of this review is to trace the natural history of glycemic alteration in women with PCOS. Methods We performed a literature review without time limit until August 2019. Inclusion criteria were studies addressing the association between impaired glucose tolerance or impaired fasting glucose or type 2 diabetes (T2D) and PCOS with at least an English abstract. The exclusion criteria were no PCOS or impaired glucose tolerance or impaired fasting glucose or T2D as outcome. The outcomes of interest were the onset of impaired glucose tolerance, impaired fasting glucose, T2D, and the progression from impaired glucose tolerance or impaired fasting glucose to T2D. Results Healthy diet and physical activity are the first-line therapy for PCOS. Treatment with metformin was associated with significant lower 2-hour postload glucose levels and with reduction in fasting glucose when compared to placebo. Thiazolidinediones were more effective in reducing fasting glucose levels compared to placebo. Metformin and pioglitazone treatments showed similar effects on fasting glucose levels. The sodium-glucose cotransporter-2 inhibitor empagliflozin did not show differences in metabolic parameters when compared to metformin. The combination therapy with metformin plus the glucagon-like peptide-1 receptor agonist liraglutide was associated with significant improvements in basal and postload glucose levels compared with only liraglutide. Likewise, a combination therapy with the dipeptidyl peptidase-4 inhibitor saxagliptin and metformin demonstrated superiority versus metformin in fasting glucose and oral glucose tolerance test normalization. Myo-inositol supplementation was associated with lower insulin levels, glucose levels, and insulin resistance when compared with placebo, metformin, or estrogen treatments. Conclusions The use of insulin-sensitizing agents, such as metformin and inositols, along with lifestyle interventions may improve the metabolic profile in PCOS women.

Time-cumulated blood pressure exposure and incident impairment of glucose tolerance and diabetes mellitus

BackgroundWith the marked increase in the prevalence of diabetes mellitus, it was the purpose of our study to assess a potential association of time-cumulated exposure to systolic (CumSBP) and of diastolic blood pressure (CumDBP) with onset of impaired glucose tolerance and diabetes mellitus.MethodsThe prospective investigation included participants of the longitudinal Kailuan Study with three baseline examinations in 2006–2007, 2008–2009 and 2010–2011, re-examination in 2012–2013, and no diabetes mellitus at baseline. Cumulative blood pressure (BP) was calculated as cumBP = [(BP1 + BP2)/2 × time1–2] + [(BP2 + BP3)/2 × time2–3]. Based on cumSBP, the study population was stratified into four groups (cumSBP < 480mmHgxyear;n = 15,339; 480mmHgxyear ≤ cumSBP < 520mmHgxyear;n = 7214; 520mmHgxyears ≤ cumSBP < 560mmHgxyears;n = 5675; and cumSBP ≥ 560mmHgxyears;n = 10,576).ResultsAfter adjusting for demographic, anthropomorphic, biochemical, socioeconomic and lifestyle parameters and as compared with the first group, the second, third and fourth group showed a significantly higher incidence of diabetes (P-trend < 0.001;hazard ratio (HR);95% confidence interval (CI):1.28(1.08,1.51),1.54(1.29,1.84), and 2.33(1.98,2.73), respectively), higher incidence of impairment of glucose tolerance (P-trend < 0.001;HR;95% CI1.17(1.02,1.33), 1.43(1.25,1.64), and 2.09(1.85,2.37), respectively), and higher incidence of diabetes developing out of an impairment of glucose tolerance (P-trend < 0.001;HR;95% CI:1.22(0.97,1.54),1.47(1.16,1.86), and 2.01(1.62,2.50), respectively). An increase in cumSBP by 10 mmHg/year or an increase in cumDBP by 5 mmHg/year was associated with a hazard ratio of incident diabetes of 1.04 (95% CI:1.03,1.04) and 1.02(1.02,1.03), respectively, with a hazard ratio of incident impairment of glucose tolerance of 1.04(95% CI:1.03,1.04) and 1.03(95% CI:1.02,1.03), respectively, and with a hazard ratio of incident diabetes developing from impairment of glucose tolerance of 1.04(95% CI:1.03,1.04) and 1.03(95% CI:1.02,1.03), respectively.ConclusionsTime-cumulated exposure to elevated blood pressure was significantly associated with an elevated incidence of impaired glucose tolerance and diabetes.

Insulin sensitivity index (ISI 0-120) from oral glucose tolerance test in healthy young adults

Background: Insulin sensitivity (IS) is the body’s systemic responsiveness to glucose and it is the measure of the ability of endogenous insulin to reduce the glucose in extracellular fluids by inhibition of gluconeogenesis and increase peripheral glucose uptake. IS reflects on the efficiency of insulin in response to glucose intake in the body. In diabetics, IS subjects are interpreted to require smaller amounts of insulin to lower blood glucose levels than someone who has low sensitivity. There is a need to detect insulin resistance (IR) in the pre-disease state, i.e., before the onset of impaired glucose tolerance (IGT). Early detection of IR or decreased IS in healthy subjects before the onset of IGT is of importance as it facilitates implementation of preventive measures in subject with such high risk. Aims and Objectives: The objective of the study is detect early occurrence of low Insulin Sensitivity in healthy young adults, using Insulin Sensitivity Index derived from OGTT. Materials and Methods: A total of 80 healthy volunteers in the age group of 18-25 years were recruited for the study, 40 subjects were siblings of diabetics and 40 subjects were siblings of non-diabetics (SND) a standard (75 g) OGTT was performed for the study. Blood samples for determination of plasma glucose and insulin levels drawn at 0 (fasting), 30, 120 min after glucose solution ingestion. Assays of fasting (basal), 30, 120 min venous plasma glucose during OGTT was performed with glucose oxidase method on site using glucose auto analyzer. The serum plasma was stored at −20°C until assayed. Corresponding specific insulin concentration was determined using radioimmunoassay (RIA) with human specific antibody RIA kit IS was calculated using physiological OGTT based mathematical models. QUICKI was derived for fasting insulin and fasting glucose values. ISI 0-120: Uses OGTT values, using only 0 and 120 min post-glucose challenge insulin and glucose concentrations. The reference values for various IR and IS indexes for our urban population with normal OGTT (n = 79) are QUICKI = 0.31 (0.20-0.52) sibling of diabetics (SD) - 0.07, ISI 0-120 = 63.62 (27.37-134.79) SD - 22.71. We observed that SD had significantly lower IS indices ISI 0-120 (56.27, P < 0.002) and a trend toward significance for QUICKI (0.29578, P < 0.056). Results: We observed that the mathematical models ISI 0-120 to be a fairly reliable tool for assessment of IS in normoglycemic young adults, compared to QUICKI. ISI 0-120 take into consideration the all the parameters of the 2 h OGTT glucose and also includes insulin into consideration for evaluation. Simple OGTT based mathematical models can be used as a reasonable alternative to measure IS or IR instead of the cumbersome glucose clamp or other expensive techniques in epidemiological or general clinical settings. Conclusion: Detection of IR in pre-disease condition in healthy individuals, allows the physician to initiate preventive measures, such as lifestyle modification, diet and exercise, thereby preventing the high-risk subjects from progressing to disease state.

Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.

Aims/hypothesisIndividuals with a low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here, we aimed to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, determine whether these changes are cell-autonomous and identify the underlying mechanisms involved.MethodsFourteen-month-old male rat offspring born to dams fed a standard protein (20%) diet or a low (8%) protein diet throughout gestation and lactation were studied. Fat distribution and adipocyte size were determined. Protein content and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and in pre-adipocytes that had undergone in vitro differentiation.ResultsThe offspring of low protein fed dams (LP offspring) had reduced visceral WAT mass, altered fat distribution and a higher percentage of small adipocytes in epididymal WAT. This was associated with reduced levels of IRS1, PI3K p110β, Akt1 and PKCζ proteins and of phospho-Akt Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, in vitro differentiated adipocytes from LP offspring showed reduced protein levels of IRβ, IRS1, PI3K p85α and p110β subunits, and Akt1. Levels of Akt Ser473 and IRS1 Tyr612 phosphorylation were reduced, while IRS1 Ser307 phosphorylation was increased.Conclusions/interpretationMaternal protein restriction during gestation and lactation changes the distribution and morphology of WAT and reduces the levels of key insulin signalling proteins in the male offspring. This phenotype is retained in in vitro differentiated adipocytes, suggesting that programming occurs via cell-autonomous mechanism(s).

Type 2 diabetes in children: Clinical aspects and risk factors.

A strong link between obesity, insulin resistance, and metabolic syndrome has been reported with development of a new paradigm to type 2 diabetes mellitus (T2DM), with some evidence suggesting that beta-cell dysfunction is present before the onset of impaired glucose tolerance. Differentiating type 1 diabetes mellitus (T1DM) from T2DM is actually not very easy and there exists a number of overlapping characteristics. The autoantibody frequencies of seven antigens in T1DM patients may turn out to be actually having T2DM patients (pre-T2DM). T2DM patients generally have increased C-peptide levels (may be normal at time of diagnosis), usually no auto-antibodies, strong family history of diabetes, obese and show signs of insulin resistance (hypertension, acanthosis, PCOS). The American Academy of Paediatrics recommends lifestyle modifications ± metformin when blood glucose is 126–200 mg/dL and hemoglobin A1c (HbA1c) <8.5. Insulin is recommended when blood glucose is >200 mg/dL and HbA1c >8.5, with or without ketosis. Metformin is not recommended if the patient is ketotic, because this increases the risk of lactic acidosis. Metformin is currently the only oral hypoglycemic that has been approved for use in children. Knowing these subtle differences in mechanism, and knowing how to test patients for which mechanism (s) are causing their diabetes mellitus, may help us eventually tailor treatment programs on an individual basis.

Assessment of insulin resistance in normoglycemic young adults

Detection of Insulin resistance (IR) in normoglycemic young subjects before the onset of Impaired Glucose Tolerance (IGT) is of importance as it affords implementation of preventive measures in such high risk subject. Very few studies have specifically evaluated for the presence of IR in younger age group with normal glucose tolerance. The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," the complicated nature of the "clamp" technique, alternatives have been sought to simplify the measurement of insulin resistance. The oral glucose tolerance test (OGTT) is one of the most commonly used methods to evaluate whole body glucose tolerance in vivo. IR & IS values of HOMA-IR, ISI 0-120, QUICKIE mathematical models derived from OGTT have been shown to produce equivalent results as in Euglycemic clamp technique we hypothesized that normoglycemic young adult who are siblings of type II diabetics (SD) probably have higher IR values than the siblings of non diabetics as they are genetically predisposed. In this study 79 normal young adult volunteers, 40 subjects with family history of diabetes (SD) and 39 subjects without family history of diabetes (SND), in the age range of 18 to 25 years were evaluated for Insulin resistance. Standard (75 g) OGTT was performed on all the study subjects after an overnight fast. Fasting (basal), 30, 120 min venous plasma glucose & Corresponding specific insulin concentration was determined by radioimmuno assay (RIA) using a human specific antibody RIA kit. In each subject, the degree of insulin resistance was estimated by various parameters of Insulin resistance & sensitivity that were calculated using physiological mathematical models like HOMA-IR, ISI0-120, IGI, QUICKIE and their formulas derived from OGTT. The mean age of the study population was 19.01 (18 to 25 years), Male: 33 (41.3%) and Female: 47 (58.8%). The normoglycemic subjects were categorized as Siblings of Diabetics (SD n = 40) and siblings of non-diabetics(SND n = 39). Both the groups were matched by physical, clinical and routine laboratory parameters and were not statistically significant different. Siblings of diabetics had a statistically significant higher values of insulin at baseline, 30 min & 120 minutes and glucose at 30 minutes. Siblings of diabetics had a significantly higher insulin resistance and lower insulin sensitivity indices as in HOMA-IR (2.01527, p < 0.017), ISIO-120 (56.27, p < 0.002) and I0/G0 ratio (0.122381, p < 0.012) and a trend towards significance for QUICKIE(0.29578, p < 0.056). Detection of insulin resistance in normoglycemic young adult subjects in pre-disease state is feasible using mathematical models like HOMA IR, ISIO-120 from OGTT. OGTT is simple and a generally acceptable test. Siblings of diabetics had higher Insulin resistance values and lower Insulin sensitivity values. Physiological models like HOMA IR, QUICKIE, I0/G0 ratio, IGI, ISIO-120 are simple & cost effective method for screening Insulin resistance. Diagnosis of Insulin resistance in pre-disease state allows initiation of preventive measures like life style modification, diet & exercise, thereby preventing the high risk subjects from progressing to disease state.

Prognostic performance of metabolic indexes in predicting onset of type 1 diabetes.

OBJECTIVEIn this investigation we evaluated nine metabolic indexes from intravenous glucose tolerance tests (IVGTTs) and oral glucose tolerance tests (OGTTs) in an effort to determine their prognostic performance in predicting the development of type 1 diabetes in those with moderate risk, as defined by familial relation to a type 1 diabetic individual, a positive test for islet cell antibodies and insulin autoantibody, but normal glucose tolerance.RESEARCH DESIGN AND METHODSSubjects (n = 186) who had a projected risk of 25–50% for developing type 1 diabetes within 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial–Type 1. Prognostic performance of the metabolic indexes was determined using receiver operating characteristic (ROC) curve and survival analyses.RESULTSTwo-hour glucose from an OGTT most accurately predicted progression to disease compared with all other metabolic indicators with an area under the ROC curve of 0.67 (95% CI 0.59–0.76), closely followed by the ratio of first-phase insulin response (FPIR) to homeostasis model assessment of insulin resistance (HOMA-IR) with an area under the curve value of 0.66. The optimal cutoff value for 2-h glucose (114 mg/dl) maintained sensitivity and specificity values >0.60. The hazard ratio for those with 2-h glucose ≥114 mg/dl compared with those with 2-h glucose <114 mg/dl was 2.96 (1.67–5.22).CONCLUSIONSThe ratio of FPIR to HOMA-IR from an IVGTT provided accuracy in predicting the development of type 1 diabetes similar to that of 2-h glucose from an OGTT, which, because of its lower cost, is preferred. The optimal cutoff value determined for 2-h glucose provides additional guidance for clinicians to identify subjects for potential prevention treatments before the onset of impaired glucose tolerance.

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.

Clinical effects of early treatment with insulin glargine in patients with cystic fibrosis and impaired glucose tolerance

Diabetes mellitus is an increasing complication of cystic fibrosis (CF), as a result of the improved life expectancy. There is clear association between diabetes and increased morbidity and mortality. Lung function and clinical status deteriorate up to 2-4 yr before the diagnosis of CF-related diabetes (CFRD). The aim of our study was to evaluate the effects, on glucose homeostasis and clinical status, of the early treatment with insulin glargine in CF patients with impaired glucose tolerance (IGT). We selected six subjects with IGT diagnosed at oral glucose tolerance test (OGTT). Median age was 18.12 yr (range 9.2-27.8). Insulin glargine was administered at the median dosage of 0.3 U/kg/day (range 0.2-0.5). After the initial adjustment of the dosage, no patient manifested hypoglycemia during treatment. Median glycosylated hemoglobin (HbA1c) did not show any significant variation during treatment: it was 5.9% at baseline (range 5.5-6.2) and 6.1% (range 5.0-6.7) at the end of follow-up (p=0.496). Median body mass index (BMI) z-score significantly increased during treatment, from -0.95 (range -3.2-+0.6) at baseline to -0.5. (range -3.0-+0.9) at the end of follow-up (p=0.026). Lung function, measured by median forced expiratory volume in the first second (FEV1%), showed a mild but significant improvement during insulin treatment. It was 72.7% at baseline (range 41.5-98.4) and 76.7% (range 42.0-106.8) at the end of follow-up (p=0.027). No significant variation was found between the number of hospitalizations for clinical exacerbation (no./patient/yr) in the last 2 yr before treatment and during follow-up. Median number at baseline was 1.95/patient/yr (range 1-3) and 2.0/patient/yr (range 1-3) at follow-up (p=0.715). Our data seem to indicate that early insulin therapy can be safe, no patient manifested hypoglycemia or other adverse effects during treatment. Insulin is an anabolic hormone implicated in both lipid and protein metabolism. The appearance of IGT out of infections can indicate an early insulin deficiency, with a potential impact on the nutritional and clinical status of the patient, even before the appearance of overt diabetes. Larger controlled trials are necessary to verify if early insulin therapy is able to reduce the deterioration of nutritional status and lung function associated with the onset of IGT.

Insulin resistance and impaired glucose tolerance in obese children and adolescents referred to a tertiary-care center in Israel

To establish the prevalence of insulin resistance and impaired glucose tolerance (IGT) and their determinants in a cohort of obese children and adolescents. A retrospective design was used. The study group included 234 patients with a body mass index (BMI) greater than the 95th percentile for age and gender and 22 patients with a BMI between the 85th and 95th percentile for age and gender referred for evaluation to a major tertiary-care center in Israel. Ages ranged from 5 to 22 y. Estimates of insulin resistance (homeostatic model assessment (HOMA-IR)); insulin sensitivity (ratio of fasting glucose (GF) to fasting insulin (IF) (GF/IF), the quantitative insulin sensitivity check index (QUICKI)), and pancreatic beta-cell function (HOMA-derived beta-cell function (HOMA %B)) were derived from fasting measurements. An oral glucose tolerance test (OGTT) was performed in 192 patients to determine the presence of IGT. Insulin resistance was detected in 81.2% of the patients, IGT in 13.5%, and silent diabetes in one adolescent girl. Only two patients with IGT also had impaired fasting glucose (IFG). The prevalence of IGT was higher in adolescents than prepubertal children (14.7 vs 8.6%). GF/IF and QUICKI decreased significantly during puberty (P<0.005), whereas HOMA-IR and HOMA %B did not. Insulin resistance and insulin sensitivity indexes were not associated with ethnicity, presence of acanthosis nigricans or family history of type 2 diabetes. Patients with obesity complications had lower insulin sensitivity indexes than those without (P=0.05). Compared with subjects with normal glucose tolerance (NGT), patients with IGT had significantly higher fasting blood glucose (85.9+/-6.5 vs 89.2+/-10.6 mg/dl, P<0.05), higher 2-h post-OGGT insulin levels (101.2+/-74.0 vs 207.6+/-129.7 microU/ml, P<0.001), a lower QUICKI (0.323+/-0.031 vs 0.309+/-0.022, P<0.05), and higher fasting triglyceride levels (117.4+/-53.1 vs 156.9+/-68.9, P=0.002). However, several of the fasting indexes except QUICKI failed to predict IGT. There was no difference between the group with IGT and the group with NGT in fasting insulin, HOMA-IR, HOMA %B or the male-to-female ratio, age, BMI-SDS, presence of acanthosis nigricans, ethnicity, and family history of type 2 diabetes. Insulin resistance is highly prevalent in obese children and adolescents. The onset of IGT is associated with the development of severe hyperinsulinemia as there are no predictive cutpoint values of insulin resistance or insulin sensitivity indexes for IGT, and neither fasting blood glucose nor insulin levels nor HOMA-IR or HOMA %B are effective screening tools; an OGTT is required in all subjects at high risk. Longitudinal studies are needed to identify the metabolic precursors and the natural history of the development of type 2 diabetes in these patients.

Low birthweight is associated with specific changes in muscle insulin-signalling protein expression

People with low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. The mechanistic basis of this phenomenon is not known. Here we investigate the effect of early growth restriction on the expression of insulin-signalling proteins in skeletal muscle in a human cohort and a rat model. We recruited 20 young men with low birthweight (mean birthweight 2702+/-202 g) and 20 age-matched control subjects (mean birthweight 3801+/-99 g). Biopsies were obtained from the vastus lateralis muscle and protein expression of selected insulin-signalling proteins was determined. Rats used for this study were male offspring born to dams fed a standard (20%) protein diet or a low (8%) protein diet during pregnancy and lactation. Protein expression was determined in soleus muscle from adult offspring. Low-birthweight subjects showed reduced muscle expression of protein kinase C (PKC)zeta, p85alpha, p110beta and GLUT4. PKCzeta, GLUT4 and p85 were also reduced in the muscle of rats fed a low-protein diet. Other proteins studied were unchanged in low-birthweight humans and in rats fed a low-protein diet when compared with control groups. We found decreased expression of specific insulin-signalling proteins in low-birthweight subjects compared to controls. These changes precede the onset of impaired glucose tolerance. The similarity of protein expression profile in the men with low birthweight compared to that of the offspring of rats fed a low-protein diet suggests that the rodent model is an accurate representation of the human situation. It also provides a potential mechanistic explanation as to why the fetal environment plays an important role in determining risk of developing type 2 diabetes.

Characteristics of Japanese Subjects Who Progress from Normal to Impaired Glucose Tolerance. Longitudinal Study Excluding Changes in Body Weight

In this retrospective longitudinal study, we focused on the clinical characteristics of Japanese individuals with recent onset impaired glucose tolerance (IGT) who have been followed up for insulin secretory function and 75-gram oral glucose tolerance test (OGTT) for more than 3 years annually before they progressed from normal glucose tolerance (NGT) to IGT. Subjects whose body weight did not show significant change for the period were selected and labeled as either NGT (no change in OGTT over 3 years) or IGT (progressors from NGT to IGT) groups (n = 24, each). We compared the basal biochemical data and response of plasma glucose and serum insulin after OGTT of the two groups. In the IGT progressors, significant increase of plasma glucose at 30 to 120 minutes during OGTT and significant decrease of HDL-cholesterol were observed since 3 years before onset of IGT. In addition to increase of serum glucose and decrease of HDL-cholesterol, serum insulin at 120 minutes during OGTT were significantly and remarkably high at onset and 3 years before onset of IGT. Plasma glucose at 30-120 minutes and serum insulin level at 120 minutes after glucose load are potentially significant predictors of progression from NGT to IGT even in subjects who do not show increase of body weight.

The roles of insulin resistance, hyperinsulinemia, and thiazolidinediones in cardiovascular disease

Although it is difficult to distinguish between the relative effects of insulin resistance and hyperinsulinemia, insulin resistance is clearly associated with significantly increased cardiovascular and cerebrovascular risk. This effect is consistent across the spectrum of worsening glycemic control, from the onset of impaired glucose tolerance to the development of clinical diabetes. It is more difficult to discriminate between the roles of elevated circulating insulin and proinsulin levels; the association between insulin levels and cardiovascular risk is weak. The thiazolidinediones (TZDs) significantly improve insulin sensitivity and exert numerous effects on the vascular bed, including improved endothelial function, decreased vascular inflammation, decreased plasma free fatty acid levels, improved dyslipidemic profiles, and inhibition of vascular smooth muscle proliferation. These findings provide increasing evidence to suggest that the TZDs may have a beneficial effect on atherosclerosis and may reduce the incidence and severity of adverse cardiovascular outcomes. These effects remain to be substantiated by the results of large outcomes studies to evaluate the impact of glycemic control and reversal of insulin resistance on cardiovascular events.

Nutrient‐Gene Interactions in Mitochondrial Function: Vitamin A Needs Are Increased in BHE/Cdb Rats

The BHE/Cdb rat has a maternally inherited mutation in the ATPase 6 mitochondrial gene that associates with impaired oxidative phosphorylation (OXPHOS) and glucose intolerance. A longevity study revealed that feeding an egg-rich (vitamin A-rich) diet delayed the onset of impaired glucose tolerance. Two experiments were conducted to test the hypothesis that BHE/Cdb rats require more dietary vitamin A than normal rats. Experiment 1 was a dose-response study examining OXPHOS in BHE/Cdb rats fed one of six levels of vitamin A. In experiment 2 BHE/Cdb and Sprague-Dawley rats were used. The rats were depleted of retinol stores, then repleted with 4 or 12 IU vitamin A/g diet. Vitamin A status was assessed in depleted, never depleted, and depleted/repleted rats. OXPHOS was optimized at 4 IU/g diet for the Sprague-Dawley rats and 12 IU/g diet for the BHE/Cdb rats. These results suggested that the criteria for vitamin intake adequacy in the BHE/Cdb rats is the optimization of mitochondrial OXPHOS. Using this criteria, we conclude that diabetes-prone BHE/Cdb rats require more dietary vitamin A than normal rats.

Past Practice of Sports and Type 2 Diabetes in Later Life

Introduction: Type 2 diabetes mellitus (T2DM) results from 2 combined abnormalities (insulin resistance and pancreatic β-cell dysfunction), which are present in variable proportion. Regular practice of sports improves insulin sensitivity, decreases atherogenic markers, and may even delay the onset of impaired glucose tolerance in at-risk individuals. Since known duration of type 2 diabetes often underestimates the true exposure to hyperglycaemia and to other atherogenic abnormalities, it is plausible to expect that regular practice of sports prior to T2DM diagnosis might favourably modify the spectrum of diabetes-related complications after diagnosis. Methods: We compared 60 male subjects who reported having practised sports on a regular basis prior to being diagnosed with T2DM (EX-group) with 96 control T2DM subjects who never practised sports, and matched for age and known diabetes duration (NEVER-group). Micro- and macro-angiopathic complications were analysed, alongside diabetic and cardiovascular drug use, prevalence of hypertension, and lipid profile. Results: Age (mean ± 1SD) was 59.5 ± 11.0 years, and known diabetes duration 10.4 ± 7.0 years. EX-subjects were aged 40 ± 14 years at the time they interrupted their sports practice, the interval between interruption and T2DM diagnosis amounting to 12 ± 10 years. There were no difference in present-day BMI (29 ± 5 kg.m−2), nor in waist diameter (103 ± 11 cm) or percent body fat (30 ± 7%) between the EX- and NEVER-groups. Metabolic control, assessed by HbA1c, was similar in both groups (8.3 ± 2.0 (EX-) vs. 8.1 ± 2.1% (NEVER-; NS)). High blood pressure (BP) was present in 53 and 58% respectively. There was no difference between groups for BP- or lipid-lowering drug(s) and drug class(es) usage. Systolic and diastolic BP were identical in both groups (145 and 85 mm Hg). Insulin sensitivity (IS) and β-cell function (β) assessed by the HOMA model (1) were similar in both groups. Thus, IS was (median [perc. 25–75]) 36 [27–58] and 37 [28–48]%, while β was 60 [32–90] and 64 [36–109]% respectively in EX- and NEVER-subjects (NS). Prevalence of micro- and macro-angiopathy, including coronary artery disease (CAD) were lower, though not significantly, in EX-subjects: 22 vs. 29% (retinopathy); 18 vs. 26% (microalbuminuria); 26 vs. 40% (peripheral neuropathy); 27 vs. 35% (macro-angiopathy); 15 vs. 25% (CAD). Total cholesterol.HDL-C−1, fasting- and inter-prandial TG were not significantly different between groups, nor was the absolute 10 year CAD excess risk estimated from Coronary Risk Chart: 12 ± 10%. Discussion: Past regular practice of sports in male subjects did not result in a significantly less severe spectrum of diabetes-related complications after a known duration of type 2 diabetes mellitus of 10 years, when compared with subjects matched for age and for diabetes duration. Nevertheless, a non-significant lesser prevalence of micro- and macro-angiopathic manifestations was found associated with past practice of sports prior to diabetes diagnosis.

Hyperinsulinemia—How Innocent a Bystander?

Hyperinsulinemia is very much in the spotlight. Debate rages as to its significance and role in the etiology not only of NIDDM, but also other morphological and metabolic risk factors for atherosclerotic cardiovascular disease, including upper-body obesity, dyslipidemia, hypertension, and hyperuricemia. Epidemiological data support a key role for hyperinsulinemia in these disorders but it is far from conclusive except for the fact that hyperinsulinemia and insulin resistance may be present many years before the onset of impaired glucose tolerance and NIDDM, and clearly play a role in their etiology. The thrifty genotype hypothesis provides a plausible basis for a better understanding of how hyperinsulinemia and insulin resistance could lead to glucose intolerance and atherosclerotic cardiovascular disease, but the detailed biochemical mechanisms remain elusive. A role for increased sympathetic nervous system activity, resulting from hypothalamic stimulation as a primary event causing hyperinsulinemia, cannot be excluded as a cause of hyperinsulinemia. The current focus on hyperinsulinemia also has resulted in closer examination of the therapy of diabetes and hypertension, emphasizing the need to avoid hyperinsulinemia in both IDDM and NIDDM individuals because of the putative risk of atherosclerotic cardiovascular disease and hypertension. There is still a paucity of epidemiological data to support a role for hyperinsulinemia in the etiology of hypertension. However, clinical practice already is being influenced by the fact that ACE inhibitors have been shown to reduce insulin resistance in clinical research studies. The research reviewed here, particularly that relating to hyperinsulinemia, insulin resistance, and cardiovascular disease risk factors, has opened new vistas for the treatment and prevention of NIDDM and atherosclerotic cardiovascular disease. Appropriate exercise clearly is associated with improved insulin sensitivity, modification of CVD risk factors, and lower prevalence of NIDDM. Upper-body obesity, the latest culprit in the field, can also be reduced by exercise. Hyperinsulinemia and insulin resistance can be detected in children, adolescents, and young adults. NIDDM can be prevented, but clearly, intervention needs to commence in childhood, and intensive risk factor intervention in subjects with NIDDM can reduce the risk of atherosclerotic cardiovascular disease. It seems paradoxical that prevention of NIDDM and atherosclerotic cardiovascular disease are now possible even though the biochemical and molecular basis of these disorders is not fully understood.

CARDIOVASCULAR RISK FACTORS AND IMPAIRED GLUCOSE TOLERANCE: THE SAN LUIS VALLEY DIABETES STUDY

Cardiovascular risk factor patterns were examined cross-sectionally in 856 Hispanic and Anglo subjects aged 20-74 years enrolled in the population-based San Luis Valley Diabetes Study of Colorado. Risk factor levels and prevalence were compared for 279 individuals with non-insulin-dependent diabetes mellitus, 89 with impaired glucose tolerance, and 488 with normal glucose tolerance. Sex-specific comparisons of continuous risk factors were made by diabetic status and ethnicity, adjusting for age using two-way analysis of covariance; similar comparisons of discrete variables were made using logistic regression. A number of vascular, metabolic, lipid, obesity-related, family history, and life-style risk factors for cardiovascular disease were examined. In general, biologic risk factors tended to be more strongly associated with diabetic status, while life-style risk factors varied more by ethnicity. Age-adjusted levels of systolic and diastolic blood pressure, hypertension history, triglyceride, and body mass index were lowest among normal subjects, intermediate for those with impaired glucose tolerance, and highest in subjects with non-insulin-dependent diabetes mellitus, while the trend was reversed for high density lipoprotein (HDL) cholesterol and its subfractions. Hispanics had lower serum uric acid levels and greater central obesity than Anglos; they were less likely to have a Type A personality, less physically active at work, and more likely to be a current smoker than Anglos. Hispanic males had a lower body mass index and a higher HDL cholesterol level than Anglo males. These results indicate that an adverse cardiovascular risk factor pattern is present not only in subjects with non-insulin-dependent diabetes mellitus but also in subjects with impaired glucose tolerance who are at increased risk of developing diabetes. This suggests that an adverse risk factor pattern may develop concurrently with or prior to the onset of impaired glucose tolerance. Future prospective studies will help to clarify the temporal sequence involved in the development of adverse cardiovascular risk factor patterns and impaired glucose tolerance.