Pre-Diabetes 1

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Pre-Diabetes

            (1952) Download

Studies in pre-diabetes

            (Jackson 1952) Download

Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose

            (Abdul-Ghani, Tripathy et al. 2006) Download

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are intermediate states in glucose metabolism that exist between normal glucose tolerance and overt diabetes. Epidemiological studies demonstrate that the two categories describe distinct populations with only partial overlap, suggesting that different metabolic abnormalities characterize IGT and IFG. Insulin resistance and impaired beta-cell function, the primary defects observed in type 2 diabetes, both can be detected in subjects with IGT and IFG. However, clinical studies suggest that the site of insulin resistance varies between the two disorders. While subjects with IGT have marked muscle insulin resistance with only mild hepatic insulin resistance, subjects with IFG have severe hepatic insulin resistance with normal or near-normal muscle insulin sensitivity. Both IFG and IGT are characterized by a reduction in early-phase insulin secretion, while subjects with IGT also have impaired late-phase insulin secretion. The distinct metabolic features present in subjects with IFG and IGT may require different therapeutic interventions to prevent their progression to type 2 diabetes.


One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes

            (Abdul-Ghani, Abdul-Ghani et al. 2008) Download

OBJECTIVE: To assess the efficacy of 1-h plasma glucose concentration and the metabolic syndrome in predicting future risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1,611 subjects from the San Antonio Heart Study, who were free of type 2 diabetes at baseline; who had plasma glucose and insulin concentrations measured at time 0, 30, 60, and 120 min during the oral glucose tolerance test (OGTT); and who had their diabetes status determined with an OGTT after 7-8 years of follow-up, were evaluated. Two models, based on glucose tolerance status, 1-h plasma glucose concentration, and presence of the metabolic syndrome, were tested in predicting the risk for type 2 diabetes at 7-8 years of follow-up. RESULTS: A cutoff point of 155 mg/dl for the 1-h plasma glucose concentration during the OGTT was used to stratify subjects in each glucose tolerance group into low, intermediate, and high risk for future type 2 diabetes. A model based upon 1-h plasma glucose concentration, Adult Treatment Panel (ATP) III criteria for the metabolic syndrome, and fasting plasma glucose, independent of 2-h plasma glucose, performed equally well in stratifying nondiabetic subjects into low, intermediate, and high risk for future type 2 diabetes and identified a group of normal glucose-tolerant subjects who were at very high risk for future type 2 diabetes. CONCLUSIONS: The plasma glucose concentration at 1 h during the OGTT is a strong predictor of future risk for type 2 diabetes. A plasma glucose cutoff point of 155 mg/dl and the ATP III criteria for the metabolic syndrome can be used to stratify nondiabetic subjects into three risk groups: low, intermediate, and high risk.

Fasting versus postload plasma glucose concentration and the risk for future type 2 diabetes: results from the Botnia Study

            (Abdul-Ghani, Lyssenko et al. 2009) Download

OBJECTIVE: The purpose of this study was to assess the efficacy of the postload plasma glucose concentration in predicting future risk of type 2 diabetes, compared with prediction models based on measurement of the fasting plasma glucose (FPG) concentration. RESEARCH DESIGN AND METHODS: A total of 2,442 subjects from the Botnia Study, who were free of type 2 diabetes at baseline, received an oral glucose tolerance test (OGTT) at baseline and after 7-8 years of follow-up. Future risk for type 2 diabetes was assessed with area under the receiver-operating characteristic curve for prediction models based up measurement of the FPG concentration 1) with or without a 1-h plasma glucose concentration during the OGTT and 2) with or without the metabolic syndrome. RESULTS: Prediction models based on measurement of the FPG concentration were weak predictors for the risk of future type 2 diabetes. Addition of a 1-h plasma glucose concentration markedly enhanced prediction of the risk of future type 2 diabetes. A cut point of 155 mg/dl for the 1-h plasma glucose concentration during the OGTT and presence of the metabolic syndrome were used to stratify subjects in each glucose tolerance group into low, intermediate, and high risk for future type 2 diabetes. CONCLUSIONS: The plasma glucose concentration at 1 h during the OGTT is a strong predictor of future risk for type 2 diabetes and adds to the prediction power of models based on measurements made during the fasting state. A plasma glucose cut point of 155 mg/dl plus the Adult Treatment Panel III criteria for the metabolic syndrome can be used to stratify nondiabetic subjects into low-, intermediate-, and high-risk groups.

Beta- and alpha-cell dysfunction in subjects developing impaired glucose tolerance: outcome of a 12-year prospective study in postmenopausal Caucasian women

            (Ahren 2009) Download

OBJECTIVE: This study assessed insulin and glucagon secretion in relation to insulin sensitivity in Caucasian women who develop impaired glucose tolerance (IGT) versus those who maintain normal glucose tolerance (NGT) over a 12-year period. RESEARCH DESIGN AND METHODS: At baseline and after 3, 8, and 12 years, glucose tolerance (75-g oral glucose tolerance test), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin and glucagon secretion (2- to 5-min responses to 5 g arginine i.v. at fasting, 14 and >25 mmol/l glucose) were determined in 53 healthy Caucasian women (aged 58 years at baseline) who all had NGT at baseline. RESULTS: During the 12-year period, 26 subjects developed IGT, whereas the remaining 27 subjects maintained NGT throughout the 12-year period. Subjects developing IGT had lower insulin sensitivity than those maintaining NGT in the tests preceding diagnosis of IGT (P < or = 0.05). When judged in relation to insulin sensitivity, beta-cell glucose sensitivity and maximal insulin secretion were lower in those who later developed IGT than in those maintaining NGT at all tests (P < or = 0.05). Furthermore, subjects who developed IGT had defective suppression of glucagon secretion by glucose in the test preceding diagnosis of IGT when they still had NGT (P < or = 0.05). CONCLUSIONS: Beta- and alpha-cell dysfunction are evident several years before diagnosis of IGT, and islet dysfunction is manifested as impaired glucose sensitivity of the beta- and alpha-cells and reduced maximal insulin secretion.


In vivo insulin sensitivity and secretion in obese youth: what are the differences between normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes?

            (Bacha, Gungor et al. 2009) Download

OBJECTIVE: Impaired glucose tolerance (IGT) represents a pre-diabetic state. Controversy continues in regards to its pathophysiology. The aim of this study was to investigate the differences in insulin sensitivity (IS) and secretion in obese adolescents with IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 12 obese adolescents with NGT, 19 with IGT, and 17 with type 2 diabetes underwent evaluation of insulin sensitivity (3-h hyperinsulinemic [80 micro/m(2)/min]-euglycemic clamp), first-phase insulin and second-phase insulin secretion (2-h hyperglycemic clamp), body composition, and abdominal adiposity. Glucose disposition index (GDI) was calculated as the product of first-phase insulin x insulin sensitivity. RESULTS: Insulin-stimulated glucose disposal was significantly lower in subjects with type 2 diabetes compared with subjects with NGT and IGT, with no difference between the latter two. However, compared with youth with NGT, youth with IGT have significantly lower first-phase insulin and C-peptide levels and GDI (P = 0.012), whereas youth with type 2 diabetes have an additional defect in second-phase insulin. Fasting and 2-h glucose correlated with GDI (r = -0.68, P < 0.001 and r = -0.73, P < 0.001, respectively) and first-phase insulin but not with insulin sensitivity. CONCLUSIONS: Compared with youth with NGT, obese adolescents with IGT have evidence of a beta-cell defect manifested in impaired first-phase insulin secretion, with a more profound defect in type 2 diabetes involving both first- and second-phase insulin. GDI shows a significantly declining pattern: it is highest in NGT, intermediate in IGT, and lowest in type 2 diabetes. Such data suggest that measures to prevent progression or conversion from pre-diabetes to type 2 diabetes should target improvement in beta-cell function.

From pre-diabetes to type 2 diabetes in obese youth: pathophysiological characteristics along the spectrum of glucose dysregulation

            (Bacha, Lee et al. 2010) Download

OBJECTIVE: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are considered pre-diabetes states. There are limited data in pediatrics in regard to their pathophysiology. We investigated differences in insulin sensitivity and secretion among youth with IFG, IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 24 obese adolescents with NGT, 13 with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ([6,6-(2)H(2)]glucose), insulin-stimulated glucose disposal (R(d), euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp), body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomography), and substrate oxidation (indirect calorimetry). RESULTS: Adolescents with NGT, pre-diabetes, and type 2 diabetes had similar body composition and abdominal fat distribution. R(d) was lower (P = 0.009) in adolescents with type 2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulin was lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2 diabetes (P < 0.001), and beta-cell function relative to insulin sensitivity (glucose disposition index [GDI]) was also lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), with a further decrease (80%) in those with type 2 diabetes (P < 0.001). GDI was the major determinant of fasting and 2-h glucose levels. CONCLUSIONS: Obese adolescents who show signs of glucose dysregulation, including abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulin secretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, they are at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity or secretion may enhance the risk for this progression.

American College Of Endocrinology Pre-Diabetes Consensus Conference: part one

            (Bloomgarden 2008) Download

American College of Endocrinology Pre-Diabetes Consensus Conference: part two

            (Bloomgarden 2008) Download

American College of Endocrinology Pre-Diabetes Consensus Conference: part three

            (Bloomgarden 2008) Download

Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance

            (Bock, Dalla Man et al. 2006) Download

Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R(d)) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S(i)) and insulin-stimulated glucose disposal (S(i)*) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R(d) since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG.

Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes

            (Brown, Sinaii et al. 2008) Download

OBJECTIVE: To determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS: Glucagon and C-peptide concentrations were determined in response to standard mixed meals in 23 patients with type 1 diabetes aged 9.4 +/- 4.6 years, beginning within 6 weeks of diagnosis, and every 3 months thereafter for 1 year. RESULTS: Glucagon secretion in response to a physiologic stimulus (mixed meal) increased by 37% over 12 months, while C-peptide secretion declined by 45%. Fasting glucagon concentrations remained within the normal (nondiabetic) reference range. CONCLUSIONS: Postprandial hyperglucagonemia worsens significantly during the first year after diagnosis of type 1 diabetes and may represent a distinct therapeutic target. Fasting glucagon values may underestimate the severity of hyperglucagonemia. The opposing directions of abnormal glucagon and C-peptide secretion over time support the link between dysregulated glucagon secretion and declining beta-cell function.

Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2

            (Brubaker and Anini 2003) Download

The proglucagon-derived peptide family consists of three highly related peptides, glucagon and the glucagon-like peptides GLP-1 and GLP-2. Although the biological activity of glucagon as a counter-regulatory hormone has been known for almost a century, studies conducted over the past decade have now also elucidated important roles for GLP-1 as an antidiabetic hormone, and for GLP-2 as a stimulator of intestinal growth. In contrast to pancreatic glucagon, the GLPs are synthesized in the intestinal epithelial L cells, where they are subject to the influences of luminal nutrients, as well as to a variety of neuroendocrine inputs. In this review, we will focus on the complex integrative mechanisms that regulate the secretion of these peptides from L cells, including both direct and indirect regulation by ingested nutrients.

Screening adults for pre-diabetes and diabetes may be cost-saving

            (Chatterjee, Narayan et al. 2010) Download

OBJECTIVE: The economic costs of hyperglycemia are substantial. Early detection would allow management to prevent or delay development of diabetes and diabetes-related complications. We investigated the economic justification for screening for pre-diabetes/diabetes. RESEARCH DESIGN AND METHODS: We projected health system and societal costs over 3 years for 1,259 adults, comparing costs associated with five opportunistic screening tests. All subjects had measurements taken of random plasma and capillary glucose (RPG and RCG), A1C, and plasma and capillary glucose 1 h after a 50 g oral glucose challenge test without prior fasting (GCT-pl and GCT-cap), and a subsequent diagnostic 75 g oral glucose tolerance test (OGTT). RESULTS: Assuming 70% specificity screening cutoffs, Medicare costs for testing, retail costs for generic metformin, and costs for false negatives as 10% of reported costs associated with pre-diabetes/diabetes, health system costs over 3 years for the different screening tests would be GCT-pl $180,635; GCT-cap $182,980; RPG $182,780; RCG $186,090; and A1C $192,261; all lower than costs for no screening, which would be $205,966. Under varying assumptions, projected health system costs for screening and treatment with metformin or lifestyle modification would be less than costs for no screening as long as disease prevalence is at least 70% of that of our population and false-negative costs are at least 10% of disease costs. Societal costs would equal or exceed costs of no screening depending on treatment type. CONCLUSIONS: Screening appears to be cost-saving compared to no screening from a health system perspective, and potentially cost-neutral from a societal perspective. These data suggest that strong consideration should be given to screening-with preventive management-and that use of GCTs may be cost-effective.

Alcohol consumption and risk of pre-diabetes and type 2 diabetes development in a Swedish population

            (Cullmann, Hilding et al. 2011) Download

Aims: Alcohol is a potential risk factor of Type 2 diabetes. However, more detailed information on effects of alcohol types and early phases of Type 2 diabetes development seems warranted. The aim of this study was to investigate the influence of alcohol consumption and specific alcoholic beverages on the risk of developing pre-diabetes and Type 2 diabetes in middle-aged Swedish men and women. Methods: Subjects, who at baseline had normal glucose tolerance (2070 men and 3058 women) or pre-diabetes (70 men and 41 women), aged 35-56 years, were evaluated in this cohort study. Logistic regression was performed to estimate the risk [odds ratio (OR) and 95% confidence interval (CI)] to develop pre-diabetes and Type 2 diabetes at 8-10 years follow-up, in relation to self-reported alcohol intake at baseline. Adjustment was performed for several risk factors. Results: Total alcohol consumption and binge drinking increased the risk of pre-diabetes and Type 2 diabetes in men (OR 1.42, 95% CI 1.00-2.03 and OR 1.67, 95% CI 1.11-2.50, respectively), while low consumption decreased diabetes risk in women (OR 0.41, 95% CI 0.22-0.79). Men showed higher risk of pre-diabetes with high beer consumption (OR 1.84, 95% CI 1.13-3.01) and of Type 2 diabetes with high consumption of spirits (OR 2.03, 95% CI 1.27-3.24). Women showed a reduced risk of pre-diabetes with high wine intake (OR 0.66, 95% CI 0.43-0.99) and of Type 2 diabetes with medium intake of both wine and spirits (OR 0.46, 95% CI 0.24-0.88 and OR 0.55, 95% CI 0.31-0.97, respectively), whereas high consumption of spirits increased the pre-diabetes risk(OR 2.41, 95% CI 1.47-3.96). Conclusion: High alcohol consumption increases the risk of abnormal glucose regulation in men. In women the associations are more complex: decreased risk with low or medium intake and increased risk with high alcohol intake.

Primary prevention of cardiovascular disease in pre-diabetes: the glass is half full and half empty

            (Dagogo-Jack 2005) Download

Metabolic syndrome/insulin resistance syndrome/pre-diabetes: new section in diabetes care

            (Davidson 2003) Download

Sex differences in endothelial function markers before conversion to pre-diabetes: does the clock start ticking earlier among women? The Western New York Study

            (Donahue, Rejman et al. 2007) Download

OBJECTIVE: We examined whether biomarkers of endothelial function, fibrinolysis/thrombosis and adiponectin, predict the progression from normal to pre-diabetes more strongly among women than men over 6 years of follow-up from the Western New York Health Study. RESEARCH DESIGN AND METHODS: In 2002-2004, 1,455 participants from the Western New York Health Study, who were free of type 2 diabetes and cardiovascular disease at baseline (1996-2001), were selected for reexamination. An incident case of pre-diabetes was defined as fasting glucose <100 mg/dl at the baseline examination and > or =100 and <126 mg/dl at the follow-up examination. Biomarkers of endothelial function (E-selectin and soluble intracellular adhesion molecule-1 [sICAM-1]), fibrinolysis/thrombosis (plasminogen activator inhibitor-1 [PAI-1]), and fasting insulin, adiponectin, and inflammation (high-sensitivity C-reactive protein) were measured in frozen (-190 degrees C) baseline samples. RESULTS: Multivariate analyses revealed higher adjusted mean values of biomarkers of endothelial dysfunction (E-selectin and sICAM-1) and fibrinolysis (PAI-1) and lower mean values of adiponectin only among women who developed pre-diabetes compared with control subjects. Formal tests for interaction between sex and case/control status were statistically significant for E-selectin (P = 0.042), PAI-1 (P = 0.001), sICAM-1 (P = 0.011), and frequency of hypertension (P < 0.001). CONCLUSIONS: These results support the concept that women who progressed from normoglycemia to pre-diabetes have greater endothelial dysfunction than men as well as more hypertension and a greater degree of fibrinolysis/thrombosis. Whether this relates to the higher risk of heart disease among diabetic women awaits further study.

Alpha cell function in health and disease: influence of glucagon-like peptide-1

            (Dunning, Foley et al. 2005) Download

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.


Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glycemia and impaired glucose tolerance: the Inter99 study

            (Faerch, Vaag et al. 2009) Download

OBJECTIVE: The aim of this study was to describe the natural history of insulin secretion and insulin sensitivity in the development of isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), and combined IFG/IGT. RESEARCH DESIGN AND METHODS: Baseline and 5-year follow-up data from the Inter99 study were used. Individuals with normal glucose tolerance (NGT) at baseline and i-IFG, i-IGT, combined IFG/IGT, or NGT at the 5-year follow-up were examined with an oral glucose tolerance test (n = 3,145). Insulin sensitivity index (ISI), homeostasis model assessment of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated. RESULTS: Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI, HOMA-IS, EPIR, and disposition index during the 5-year follow-up. CONCLUSIONS: A stationary reduced insulin secretion followed by a decline in primarily hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack of beta-cell compensation is associated with the development of i-IGT. Thereby, i-IFG and i-IGT appear to result from different underlying mechanisms, which may have implications for the prevention and treatment of the diabetes that succeeds them.

Defining and characterizing the progression of type 2 diabetes

            (Fonseca 2009) Download

Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence

            (Ford, Zhao et al. 2010) Download

OBJECTIVES: Our objective was to estimate the magnitude of the relative risk (RR) for cardiovascular disease associated with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) from published prospective observational studies. BACKGROUND: Hyperglycemia is a known risk factor for cardiovascular disease. However, the magnitude of the RR for cardiovascular disease associated with IFG and IGT is unclear. METHODS: We searched PubMed from 1997 through 2008 for relevant publications and performed a meta-analysis. RESULTS: In 18 publications with information about IFG (110 to 125 mg/dl) (IFG 110), estimates of RR ranged from 0.65 to 2.50. The fixed-effects summary estimate of RR was 1.20 (95% confidence interval [CI]: 1.12 to 1.28). In 8 publications with information about IFG (100 to 125 mg/dl) (IFG 100), estimates of RR ranged from 0.87 to 1.40. The fixed-effects summary estimate of RR was 1.18 (95% CI: 1.09 to 1.28). In 8 publications with information about IGT, estimates of RR ranged from 0.83 to 1.34. The fixed-effects summary estimate of RR was 1.20 (95% CI: 1.07 to 1.34). Five studies combined IFG and IGT, yielding a fixed-effects summary estimate of RR of 1.10 (95% CI: 0.99 to 1.23). No significant difference between the summary estimates for men and women were detected (IFG 110: men: 1.17 [95% CI: 1.05 to 1.31], women: 1.30 [95% CI: 1.10 to 1.54]; IFG 100: men: 1.23 [95% CI: 1.06 to 1.42], women: 1.16 [95% CI: 0.99 to 1.36]). CONCLUSIONS: Impaired fasting glucose and IGT are associated with modest increases in the risk for cardiovascular disease.

Pre-diabetes, insulin resistance, inflammation and CVD risk

            (Haffner 2003) Download

There is accumulating evidence that insulin resistance in the pre-diabetic state is associated with the presence of additional cardiovascular risk factors and increased incidence of cardiovascular disease (CVD). There is also accumulating evidence indicating that chronic sub-clinical inflammation as measured by such inflammatory markers as C-reactive protein (CRP) is associated with insulin resistance and other features of the insulin resistance syndrome, increased risk of development of type 2 diabetes and increased cardiovascular event risk. Insulin-sensitizing agents may have greater effects in reducing cardiovascular risk than secretagogues in the pre-diabetic state, and glitazones have been found to decrease CRP levels in patients with diabetes. Statins also reduce CRP levels. Efforts to reduce CVD should include increased emphasis on improving glycaemic control, preventing development of diabetes and addressing cardiovascular risk factors in the pre-diabetic state.

Impact of glucagon response on postprandial hyperglycemia in men with impaired glucose tolerance and type 2 diabetes mellitus

            (Henkel, Menschikowski et al. 2005) Download

Glucagon is the physiological antagonist of insulin. Postprandial (pp) hyperglycemia in impaired glucose tolerance (IGT) and in type 2 diabetes mellitus (T2DM) may also depend on irregularities in glucagon secretion. This study investigated the glucagon excursion after a lipid-glucose-protein tolerance test in subjects with different stages of glucose intolerance. We also analyzed the relationship between pp glucagon secretion and hyperglycemias. A total of 64 men (27 healthy subjects with normal glucose tolerance [NGT], 15 with IGT, and 22 with T2DM) were examined. Plasma glucose (PG), insulin, proinsulin, free fatty acids, and triglycerides were measured in the fasting state and at 30 minutes and 2, 3, 4, and 6 hours after the intake of the test meal, which contained 126 g carbohydrates, 92 g fat, and 17 g protein. Postprandial concentrations of metabolic parameters were calculated as area under the curve (AUC). Glucagon was measured in the fasting state and at 30 minutes and 2 and 4 hours pp. Early glucagon increment was defined as glucagon at 30 minutes minus fasting glucagon. The insulin response was quantified as insulin increment divided by PG increment in the corresponding time. Insulin resistance was calculated using lomeostasis model assessment (HOMA). Fasting glucagon was significantly increased in IGT vs NGT (P<.05), and early glucagon increment was significantly higher in T2DM vs NGT and IGT (P<.05). The 2-hour glucagon concentration after the load (AUC) was increased in IGT and T2DM vs NGT (P<.05). Early glucagon increment and the 2-hour AUC of glucagon were strongly correlated to pp glycemia (r=0.494 and P=.001, and r=0.439 and P=.003, respectively). An inverse correlation was observed between early glucagon increment and insulin response at 30 minutes and 2 hours after the meal load (r=-0.287 and P=.026, and r=-0.435 and P=.001, respectively). The 2-hour AUC of glucagon was significantly associated with insulin resistance (r=0.354, P=.020). Multivariate analysis revealed 2-hour insulin response and early glucagon increment as significant independent determinants of the AUC of PG in IGT (R=0.787). In T2DM, 2-hour insulin response, insulin resistance, and early glucagon increment were significant determinants of the AUC of PG (R=0.867). Our study suggests an important role for the irregularities in glucagon response in the pp glucose excursion after a standardized oral mixed meal in IGT and in T2DM. According to our data, a bihormonal imbalance starts before diabetes is diagnosed. Prospective studies are needed to evaluate the impact of glucagon on the progression of glucose intolerance and the possible effects of medicinal suppression of glucagon increment to prevent the progression of glucose tolerance.

Prevalence, diagnosis, and treatment of impaired fasting glucose and impaired glucose tolerance in nondiabetic U.S. adults

            (Karve and Hayward 2010) Download

OBJECTIVE: To estimate the rates of prevalence, diagnosis, and treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A representative sample of the U.S. population (the National Health and Nutrition Examination Survey [NHANES]) from 2005-2006 including 1,547 nondiabetic adults (>18 years of age) without a history of myocardial infarction was assessed to determine the proportion of adults who met the criteria for IFG/IGT, and the proportion of IFG/IGT subjects who: 1) reported receiving a diagnosis from their physicians; 2) were prescribed lifestyle modification or an antihyperglycemic agent; and 3) were currently on therapy. We used multivariable regression analysis to identify predictors of diagnosis and treatment. RESULTS: Of the 1,547 subjects, 34.6% (CI 30.3-38.9%) had pre-diabetes; 19.4% had IFG only; 5.4% had IGT only, and 9.8% had both IFG and IGT. Only 4.8% of those with pre-diabetes reported having received a formal diagnosis from their physicians. No subjects with pre-diabetes received oral antihyperglycemics, and the rates of recommendation for exercise or diet were 31.7% and 33.5%, respectively. Among the 47.7% pre-diabetic subjects who exercised, 49.4% reported exercising for at least 30 min daily. CONCLUSIONS: Three years after a major clinical trial demonstrated that interventions could greatly reduce progression from IFG/IGT to type 2 diabetes, the majority of the U.S. population with IFG/IGT was undiagnosed and untreated with interventions. Whether this is due to physicians being unaware of the evidence, unconvinced by the evidence, or clinical inertia is unclear.

Indexes of beta-cell function from the oral glucose tolerance test can modestly predict pancreatic beta-cell area in Korean

            (Kim, Kim et al. 2011) Download

AIMS: Pancreatic beta-cell function indexes have been suggested using the oral glucose tolerance test (OGTT). Here, we investigated whether beta-cell function index from the OGTT reflects pancreatic beta-cell area in Korean patients. METHODS: The study consisted of 45 patients who underwent pancreatectomies. Before operation, a 75-g OGTT was performed. Immunohistochemical staining was performed, and indexes of beta-cell function from the OGTT data were compared with the pancreatic beta-cell area. RESULTS: The beta-cell area of the pancreas was 1.07 +/- 0.33% in the normal glucose tolerance group, 1.71 +/- 0.85% in the pre-diabetes group (impaired glucose tolerance and impaired fasting glucose), and 1.08 +/- 0.57% in the diabetes group. The beta-cell area of the pre-diabetes group was significantly higher than that of the diabetes group. Pancreatic beta-cell area showed a significant correlation with a homeostasis model assessment of beta-cell function (r=0.358, P=0.016), disposition index (r=0.336, P=0.024), fasting glucose (r=-0.359, P=0.015), and the C-peptide/glucose 30 min ratio (r=0.319, P=0.035). CONCLUSIONS: Some parameters of beta-cell function from the OGTT showed a significant relationship with the beta-cell area of pancreas.


A prospective study of uric acid by glucose tolerance status and survival: the Rancho Bernardo Study

            (Kramer, von Muhlen et al. 2010) Download

OBJECTIVES: Little is known about uric acid (UA) levels and mortality in the context of glycaemia. We examined whether serum UA levels predict all-cause and cardiovascular disease (CVD) mortality differentially in older adults by glucose tolerance status. DESIGN AND METHODS: Between 1984 and 1987, 2342 community-dwelling men and women had an oral glucose tolerance test, UA measurement, and assessment of traditional CVD risk factors. We defined glucose tolerance status as normoglycaemia (NG), pre-diabetes (pre-DM), and type 2 diabetes mellitus (T2DM). Ninety per cent were followed for vital status up to 23 years. Death certificates were coded using the Ninth International Classification of Diseases. RESULTS: Baseline age was 69.5 years; 44.4% were men. At baseline 939 had NG, 957 pre-DM, and 446 T2DM. The mean UA by glucose tolerance status was 327.1, 362.8, and 374.7 micromol L(-1). During follow-up, there were 1318 deaths 46.8% attributed to CVD. In Cox-regression analysis, each 119 micromol L(-1) (2 mg dL(-1)) increment in UA levels predicted an increased hazard ratio (HR) for all-cause deaths independent of age, smoking, body mass index, alcohol, physical activity, diuretic use and estimated glomerular filtration rate in all groups (NG: HR 1.25 95% CI 1.06-1.47, P =0.005; pre-DM: HR 1.20 95% CI 1.06-1.37, P = 0.04; T2DM: HR 1.20 95% CI 1.01-1.47, P = 0.04). After adjusting for CVD risk factors, the UA association with CVD mortality was significant only in the pre-DM and T2DM groups. CONCLUSION: All-cause mortality was independently associated with UA in all groups, but UA predicted CVD mortality only in those with abnormal glucose tolerance.

Contribution of different mechanisms to pancreatic beta-cell hyper-secretion in NOD mice during pre-diabetes

            (Liang, Du et al. 2011) Download

The development of insulin-dependent diabetes mellitus (IDDM) results from the selective destruction of pancreatic beta-cells. Both humans and spontaneous models of IDDM, such as NOD mice, have an extended pre-diabetic stage. Dynamic changes in beta-cell mass and function during pre-diabetes, such as insulin hyper-secretion, remain largely unknown. In this paper, we evaluated pre-diabetic female NOD mice at different ages (6, 10 and 14 weeks old) to illustrate alterations in beta-cell mass and function as disease progressed. We found an increase in beta-cell mass in 6-week-old NOD mice that may account for improved glucose tolerance in these mice. As NOD mice aged, beta-cell mass progressively reduced with increasing insulitis. In parallel, secretory ability of individual beta-cells was enhanced due to an increase in the size of slowly releasable pool (SRP) of vesicles. Moreover, expression of both SERCA2 and SERCA3 genes were progressively down-regulated, which facilitated depolarization-evoked secretion by prolonging Ca(2+) elevation upon glucose stimulation. In summary, we propose that different mechanisms contribute to the insulin hyper-secretion at the different ages of pre-diabetic NOD mice, which may provide some new ideas concerning the progression and management of type I diabetes.


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