Severity of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus: Relationship between Nongenetic Factors and PNPLA3/HSD17B13 Polymorphisms.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is high, though its severity is often underestimated. Our aim is to provide an estimate of the prevalence of severe NAFLD in T2DM and identify its major predictors. METHODS: T2DM patients (n=328) not previously known to have NAFLD underwent clinical assessment, transient elastography with measure of liver stiffness (LS) and controlled attenuation parameter (CAP), and genotyping for patatin like phospholipase domain containing 3 (PNPLA3) and 17ß-hydroxysteroid-dehydrogenase type 13 (HSD17B13). RESULTS: Median LS was 6.1 kPa (4.9 to 8.6). More than one-fourth patients had advanced liver disease, defined as LS ≥7.9 kPa (n=94/238, 29%), and had a higher body mass index (BMI) than those with a LS <7.9 kPa. Carriage of the G allele in the PNPLA3 gene was associated with higher LS, being 5.9 kPa (4.7 to 7.7) in C/C homozygotes, 6.1 kPa (5.2 to 8.7) in C/G heterozygotes, and 6.8 kPa (5.8 to 9.2) in G/G homozygotes (P=0.01). This trend was absent in patients with ≥1 mutated HSD17B13 allele. In a multiple linear regression model, BMI and PNPLA3 genotype predicted LS, while age, gender, disease duration, and glycosylated hemoglobin did not fit into the model. None of these variables was confirmed to be predictive among carriers of at least one HSD17B13 mutated allele. There was no association between CAP and polymorphisms of PNPLA3 or HSD17B13. CONCLUSION: Advanced NAFLD is common among T2DM patients. LS is predicted by both BMI and PNPLA3 polymorphism, the effect of the latter being modulated by mutated HSD17B13.

Improvement of insulin sensitivity in diabetic and non diabetic patients with chronic hepatitis C treated with direct antiviral agents.

BACKGROUND: The increased incidence of type 2 diabetes mellitus among hepatitis C virus (HCV) infected patients is likely due to viral-induced insulin resistance (IR). Indeed, control of diabetes in these patients benefits of successful antiviral treatment; whether the same applies to subtler alterations of glucose metabolism is unknown. We aimed to fill this gap. METHODS: The study population included 82 HCV-RNA positive patients (48 males, median age 66 years, 73 with advanced fibrosis, 41 HCV-1b), attending the liver clinic of an academic hospital to receive direct antivirals. None was previously known to be diabetic. All underwent a standard oral glucose tolerance test (OGTT) before antiviral treatment and right after its conclusion. RESULTS: At baseline, the majority of patients had evidence of abnormal glucose metabolism (N. = 45, 55%; impaired fasting glucose 10%, impaired glucose tolerance16%, both the above 12%, 17% diabetes), while only 37 (45%) were normally glucose tolerant (NGT). At the end of treatment, HCV-RNA quantification was below the detection threshold (HCV-RNA <12 UI/ml), for all patients enrolled. A significant decrease in glucose and insulin plasma concentrations was observed, leading to a significant reduction in Homeostasis Model Assessment (HOMA)-IR (from 3.42 [2.66-5.38] to 2.80 [1.78-3.95];p<0.001) and a corresponding increase in insulin sensitivity (ISI Belfiore from 0.49 [0.26-0.75] to 0.64 [0.42-0.91];p<0.001), despite a significant reduction in insulin secretion (EFP Stumvoll from 1363 [959-1730] to 1264 [976-1588];p = 0.027). Importantly, HOMA-IR reduction occurred also in the subgroup of NGT patients (p = 0.017). The number of NGT patients increased to 53, 65% (p = 0.013) paralleled by a reduced number of those satisfying criteria for prediabetic conditions (31 (38%) vs. 17 (21%); p = 0.025). CONCLUSIONS: Glucose metabolism parameters of HCV infected patients improve early after antiviral treatment, with benefits that are not limited to diabetics. These findings confirm how deep and widespread is the impairment of insulin pathways exerted by HCV infection.

Oral glucose tolerance test-based calculation identifies different glucose intolerance phenotypes within the impaired fasting glucose range.

AIMS/INTRODUCTION: The conventional oral glucose tolerance test (OGTT) cannot detect future diabetics among isolated impaired fasting glucose (is-IFG) nor normal glucose tolerant (NGT) groups. By analyzing the relationship between fasting (FPG) and 2-h plasma glucose (2hPG), the present study identifies is-IFG subjects liable to worsening glucose homeostasis. MATERIALS AND METHODS: Oral glucose tolerance test was carried out in 619 patients suffering from obesity, hypertension or dyslipidemia, whose FPG was in the 100-125 mg/dL range. We calculated the percentage increment of 2hPG with respect to FPG (PG%) in these patients using the formula: ([2hPG - FPG] / FPG) × 100. Differences in ß-cell function within is-IFG patients were assessed by estimated insulin sensitivity index (EISI), first-phase insulin release (1stPH) and 1stPH/1/EISI (1stPHcorrected). RESULTS: Diabetes was diagnosed in 69 patients (11.2%), combined IFG/impaired glucose tolerance (IGT) in 185 patients (29.9%) and is-IFG in 365 patients (58.9%). Is-IFG was subdivided into PG% tertile groups: the percentage of females increased from 25% in the lowest to 45.2% in the highest tertile (χ(2) = 18.7, P < 0.001). Moving from the lowest to the highest PG% tertile group, insulin and 2hPG concentrations rose, whereas FPG, EISI, and 1stPHcorrected decreased progressively and significantly. Furthemore, PG% correlated inversely with EISI (r = -0.44, P < 0.0001) and 1stPHcorrected (r = -0.38, P < 0.0001). CONCLUSIONS: Oral glucose tolerance test does differentiate the great heterogeneity in metabolic disorders of patients with FPG 100-125 mg/dL. Furthermore, PG% can expand the diagnostic power of OGTT in the is-IFG range by distinguishing metabolic phenotypes very likely to herald different clinical risks.

Impaired glucose metabolism in hypertensive patients with/without the metabolic syndrome.

BACKGROUND: In hypertension clinics, screening patients for the metabolic syndrome (MetS) is common practice, while performing the cumbersome oral glucose tolerance test (OGTT) is not. How large is the underestimation of diabetes and prediabetes that ensues is unknown. METHODS: We recruited N=1397 patients with essential arterial hypertension who underwent a 75-g OGTT and were classified as normally glucotolerant (NGT) or having impaired glucose metabolism (IGM), and as affected or not by MetS (ATPIII criteria). The agreement between the OGTT and the ATPIII criteria in attributing a high cardiovascular risk was estimated by matching the categories of MetS and no-MetS with NGT and IGM. RESULTS: n=677/1397 patients (48%) satisfied criteria for MetS, while n=757/1397 (54%) had an IGM. MetS and IGM were both present in n=512/1397 patients (36.6%), and both absent in n=475/1397 (34%). Further n=410/1397 patients (29%) were discordant for the two conditions: n=165/410 (40%) had the MetS but were NGT, and n=245/410 (60%) had IGM but no MetS. Among IGM patients, n=168/757 (22%; of which 45 had no MetS) received a new diagnosis of diabetes based on OGTT criteria. Among all discordant patients, those with IGM and no MetS were more commonly males (p<0.001), and had older age (p<0.001) and lower body mass index (p<0.05). CONCLUSIONS: Among patients with hypertension, the estimate of the prevalence of diabetes and prediabetes, hence of the global cardiovascular risk, can be seriously flawed unless an OGTT is performed. Our results support a wider use of the OGTT in the management of hypertension.

Treating high blood pressure: is reaching the target more important than the means? Yes, the target is more important.

The effectiveness of hypertension treatments is attributed either to the change in blood pressure, independent of the means used, or to an important contribution of appropriate drug selection: this debate probably stems from an inappropriate comparison. Treating essential hypertension in relatively healthy patients without advanced vascular disease and co-morbidities affords cardio-vascular protection by the lowering of the mechanical shear stress determined by blood pressure per se: thus, lowering blood pressure is the critical step, while the methods used can only differ through side effects. This treatment is, in fact, a lifetime prophylaxis, as hypertension, rather than a disease, is a symptom affecting one tail of the Gaussian distribution of blood pressure across the normal population. Treating hypertension in the context of diseases, like diabetes mellitus, congestive heart failure, left ventricular hypertrophy, and advanced atherosclerosis, would be improper if focused on just one symptom, while the appropriate treatment must include options which exhibit a more extended profile to include effectiveness on cardiac hypertrophy, insulin resistance, cardiac output, and systemic hemodynamics: thus, drugs may be different in their effectiveness and in the cardio-vascular protection afforded, even though the trials quoted in favour of this thesis were designed to compare drugs in their ability to lower blood pressure rather than in improving the overall complex clinical derangements. In conclusion, while the answer to the question is a sharp YES when dealing with primary prevention, it might be a NO, still clouded by contradictory and inconclusive evidence when dealing with secondary prevention and/or treatment of complex disease conditions and co-morbidities.

Comparison between HOMA-IR and ISI-gly in detecting subjects with the metabolic syndrome.

BACKGROUND: To verify whether, as index of insulin resistance, ISI-gly (insulin sensitivity index) is more efficient than HOMA-IR (homeostatic model assessment) or QUICKI (quantitative insulin sensitivity check index) in detecting patients with the metabolic syndrome. METHODS: Excluding patients with known diabetes, endocrine, liver and kidney diseases, we enrolled 553 subjects who were screened for metabolic abnormalities. After 5 days of a balanced weight maintenance diet, we performed an OGTT (oral glucose tolerance test) and measured fasting and 2-h postload blood sugar and insulin, from which we calculated ISI-gly, HOMA-IR and QUICKI, stratifying patients in tertiles. Statistical comparisons were performed for a number of metabolic variables between tertiles of the same index, as well as between tertiles of different indexes presumably expressing identical insulin resistance. RESULTS: All variables reflecting the metabolic syndrome were significantly more altered in the top as compared to the intermediate and the lowest tertile for HOMA-IR, the opposite for ISI-gly. Comparing homologous measurements of the top tertile of HOMA-IR with the lowest tertile of ISI-gly (presumably expressing identical insulin resistance), fasting glucose and insulin were significantly higher, while 2-h OGTT values were significantly lower. The opposite occurred comparing the lowest HOMA-IR to the highest ISI-gly tertile, the diagnostic predictive values of the latter in detecting metabolic derangements being also higher. Data from QUICKI 1st to 3rd tertiles exactly matched those obtained from HOMA-IR 3rd to 1st tertile. CONCLUSIONS: ISI-gly, which includes postload glucose and insulin concentrations, provides a more accurate estimate of whole-body insulin sensitivity than HOMA-IR or QUICKI, derived from fasting measurements only, thus constituting a more sensitive tool for screening and preventing metabolic abnormalities.

The significance of impaired fasting glucose versus impaired glucose tolerance: importance of insulin secretion and resistance.

OBJECTIVE: The American Diabetes Association recommended substituting 2hBS (glycemia at the second hour of an oral glucose tolerance test [OGTT]) for fasting blood glucose (FBS) in screening for glucose intolerance. It is debated whether these tests measure the same abnormality and relate to defective insulin secretion or resistance. This study examines the diagnostic effectiveness of FBS versus 2hBS and their relationship with insulin secretion and resistance. RESEARCH DESIGN AND METHODS: Based on history or physical findings suggesting glucose intolerance, we enrolled 398 unselected subjects admitted to a general Internal Medicine ward. After 5 days of a weight-maintaining diet, FBS, 2hBS, and insulin were measured during OGTT. The homeostatic model assessment was used to assess beta-cell function and insulin resistance. RESULTS: Excluding 19 patients with diabetes (5%), we identified 284 subjects with normal glucose tolerance (NGT), 22 with isolated impaired fasting glucose (IFG), 59 with isolated impaired glucose tolerance (IGT), and 14 with associated IFG/IGT. The sensitivity of FBS in predicting 2hBS was 19%, specificity 93%. Positive and negative predictive values were 39% and 83%, respectively. Insulin resistance was absent in NGT and IFG and markedly elevated in IGT and IFG/IGT, whereas defective insulin release was significant only in isolated IFG. CONCLUSIONS: In unselected patients, elevated FBS depends primarily on defective insulin secretion, and impaired 2hBS on insulin resistance. Because these tests measure different alterations, they are useful in combination.