Giuseppe Seghieri

Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients

OBJECTIVE—To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS—Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20–61 kg/m2). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS—The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27–0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. CONCLUSIONS—Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.

Plasma and platelet taurine are reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine supplementation.

Plasma and platelet taurine concentrations were assayed in 39 patients with insulin-dependent diabetes mellitus (IDDM) and in 34 control subjects matched for age, sex, and both total and protein-derived daily energy intake. Platelet aggregation induced by arachidonic acid in vitro at baseline and after oral taurine supplementation (1.5 g/d) for 90 d was also studied. Plasma and platelet taurine concentrations (mean +/- SEM) were lower in diabetic patients (65.6 +/- 3.1 mumol/L, or 0.66 +/- 0.07 mol/g protein) than in control subjects (93.3 +/- 6.3 mumol/L, or 0.99 +/- 0.16 mol/g protein, P < 0.01). After oral supplementation, both plasma and platelet taurine concentrations increased significantly in the diabetic patients, reaching the mean values of healthy control subjects. The effective dose (mean +/- SEM) of arachidonic acid required for platelets to aggregate was significantly lower in diabetic patients than in control subjects (0.44 +/- 0.07 mmol compared with 0.77 +/- 0.02 mmol, P < 0.001, whereas after taurine supplementation it equaled the mean value for healthy control subjects (0.72 +/- 0.04 mmol). In in vitro experiments, taurine reduced platelet aggregation in diabetic patients in a dose-dependent manner, whereas 10 mmol taurine/L did not modify aggregation in healthy subjects.

Taurine supplementation and diabetes mellitus.

Purpose of reviewTaurine is a semi-essential sulphur amino acid derived from methionine and cysteine metabolism. It has been evaluated either in experimental or clinical type 1 and 2 diabetes mellitus and insulin resistance. One form of experiment has included the possibility that perinatal taurine administration could prevent diabetes mellitus and/or insulin resistance. Recent findingsExperimental data suggest strongly that taurine could have beneficial effects in type 1 diabetes mellitus, and could generally reduce organ lipid peroxidation and plasma lipids. Interestingly, retina, lens and nerves seem to respond better to taurine than other organs such as kidneys. It has been shown in some experimental models that in type 2 diabetes mellitus and insulin resistance there is alteration in taurine homeostasis. Taurine could prevent the onset of diabetes mellitus in NOD mice and postnatal taurine modifies the glucose-loading curves in adults. However, the clinical studies are too small and too short to have any real significance. SummaryFurther experimental and clinical studies are required to evaluate taurines possible therapeutic potential. Careful attention has to be paid in the selection of animal species, in standardization of taurine concentrations and patient selection. Moreover, care must also be given to the metabolic state, presence of complications, duration of supplementations and selection of the right end-points.

Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes

CONTEXT Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known. OBJECTIVE The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors. DESIGN, SETTING, AND PATIENTS We administered a mixed meal with glucose tracers ([6,6-(2)H(2)]-glucose infused, [1-(2)H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A(1c) = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion. INTERVENTION We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n = 25) or placebo (n = 22). RESULTS Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = -353 ± 915 vs. +146 ± 601 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol · min(-1) · m(-2) · mm(-1); median [interquartile range]) and glucagon AUC decreased (19.6 ± 7.5 to 17.3 ± 7.1 ng · ml(-1) · 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased β-cell glucose sensitivity also during the isoglycemic test. CONCLUSIONS Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to both oral and iv glucose.

Are the available experimental models of type 2 diabetes appropriate for a gender perspective

Several experimental models have so far been developed to improve our knowledge of the pathogenetic mechanisms of type 2 diabetes mellitus (T2D), to determine the possible pharmacological targets of this disease and to better evaluate diabetes-associated complications, e.g. the cardiovascular disease. In particular, the study of T2D gained the attention of several groups working with different animal species: rodents, cats or pigs, as well as other non-human primate species. Each of these species provided useful and different clues. However, T2D has to be considered as a gender-associated disease: sex differences play in fact a key role in the onset as well as in the progression of the disease and a higher mortality for cardiovascular diseases is detected in diabetic women with respect to men. The results obtained from all the available animal models appear to only partially address this issue so that the search for more precise information in this respect appears to be mandatory. In this review we summarize these concepts and literature in the field and propose a reappraisal of the various animal models for a study of T2D that would take into consideration a gender perspective.

Indications of reduced pulmonary function in type 1 (insulin-dependent) diabetes mellitus☆

Abnormalities of pulmonary function tests have been described in type 1 (insulin-dependent) diabetes mellitus (IDDM). To better characterise such abnormalities and to verify whether these latter are associated with the presence of diabetic microvascular disease we compared 23 non-smoking patients who had IDDM with 24 non-smoking healthy control subjects strictly matched for sex, age, and body mass index. Compared with controls, diabetic patients had a reduced forced vital capacity (FVC) (87.5 +/- 13.1% vs. 96.4 +/- 13.6% of the predicted; P = 0.03) and forced expiratory volume in 1 s (FEV1) (90.5 +/- 17.7% vs. 101.2 +/- 13.2% of the predicted; P = 0.02). While within the group of patients the presence of retinopathy and autonomic neuropathy were not associated with modifications of pulmonary function tests, those with altered urinary albumin excretion rate (AER > or = 20 micrograms/min; range 21-589) (n = 7) had a significantly lower pulmonary diffusion capacity (DLCO) than the 16 normoalbuminuric subjects (62.6 +/- 7.2% vs. 88.7 +/- 20.1% of the predicted; P = 0.01). Moreover, in the group of patients, DLCO was inversely related with AER (r = -0.43; P = 0.04). In conclusion, IDDM is characterised by reduced FVC and FEV1, while a significant decrease in DLCO may be considered as selectively associated with renal disease.

Normal Glucose Tolerance and Gestational Diabetes Mellitus What is in between

OBJECTIVE— The aim of this article was to define the metabolic phenotype of pregnant women with one abnormal value (OAV) during an oral glucose tolerance test (OGTT) and to test whether OAV could be considered metabolically comparable to gestational diabetes mellitus (GDM) or a specific entity between GDM and normal pregnancy. RESEARCH DESIGN AND METHODS— After 100-g 3-h OGTTs, 4,053 pregnant women were classified as having GDM, OAV, or normal glucose tolerance (NGT). Those with OAV were subdivided into three subgroups: fasting hyperglycemia (one abnormal value at fasting during an OGTT), 1-h hyperglycemia (one abnormal value at 1 h during an OGTT [1h-OAV]), or 2- or 3-h hyperglycemia (one abnormal value at 2 or 3 h during an OGTT). As derived from the OGTT, we measured insulin sensitivity (insulin sensitivity index [ISI] Matsuda) and insulin secretion (homeostasis model assessment for the estimation of β-cell secretion [HOMA-B], first- and second-phase insulin secretion). The product of the first-phase index and the ISI was calculated to obtain the insulin secretion–sensitivity index (ISSI). RESULTS— GDM was diagnosed in 17.9% and OAV in 18.7% of pregnant women; women with GDM and OAV were older and had higher BMI and serum triglyceride levels than those with NGT (all P < 0.05). Women with NGT had the highest ISI followed by those with OAV (−21.7%) and GDM (−32.1%). HOMA-B results were comparable with those for OAV and GDM but significantly (P < 0.01) lower than those for NGT; first- and second-phase insulin secretion appeared progressively reduced from that in women with NGT to that in women with OAV and GDM (P < 0.01). ISSI was higher in women with NGT than in women with either OAV (−34%) or GDM (−51.7%) (P < 0.001). Among OAV subgroups, the 1h-OAV subgroup showed the lowest ISSI (P < 0.05). CONCLUSIONS— OAV and GDM are clinically indistinguishable, and both groups are different from women with NGT. Women with GDM and OAV showed impaired insulin secretion and insulin sensitivity, although these defects are more pronounced in women with GDM. Compared with other OAV subgroups, 1h-OAV could be considered a more severe condition.

Effect of Insulin on Systemic and Renal Handling of Albumin in Nondiabetic and NIDDM Subjects

Insulin resistance and hyperinsulinemia cluster with microalbuminuria in both diabetic and nondiabetic subjects, but the mechanism underlying this association is unknown. To test the hypothesis that insulin influences protein permeability, we measured the albumin transcapillary escape rate (TER) by the 131I-labeled albumin technique in 12 healthy volunteers and 12 normoalbuminuric NIDDM patients (fasting plasma glucose, 10.9 ± 1.3 mmol/l) during 4 h of isoglycemia with high (1.1 mU · min−1 · kg−1) or, on a different day, low (0.1 mU · min−1 · kg−1) insulin infusion. In both patients and control subjects, high insulin was associated with a 7% decrease in blood volume (P = 6.006) and a 6% decrease in diastolic blood pressure (P < 0.02), these two changes being related to one another (r = 0.56, P < 0.01). Basal albumin TER was similar in patients (8.4 ± 0.5% · h−1) and control subjects (7.7 ± 0.7% · h−1) and was not significantly changed by high insulin in either group (patients vs. control subjects, 7.3 ± 0.9 vs. 6.2 ± 0.4% · h−1; NS vs. low insulin). In contrast, high insulin increased renal albumin excretion (from 3.6 ± 0.8 to 5.4 ± 1.1 μg/min, P < 0.01) and clearance rate (0.09 ± 0.02 to 0.13 ± 0.03 μl/min, P < 0.001) in patients but not in control subjects. To localize the effect of insulin along the nephron, we measured the urinary excretion of N-acetyl-β-D-glucosaminidase (β-NAG), released by the proximal tubule; retinol-binding protein (RBP), reabsorbed by the proximal tubule; and Tamm-Horsfall protein (THP) and epidermal growth factor (EGF), both secreted by the distal tubule. For both β-NAG and RBP, but not EGF or THP, insulin enhanced urinary excretion (diabetics vs. controls: β-NAG, 0.48 vs. −0.15 μU/min [P = 0.03]; RBP, 78 vs. −32 ng/min [P = 0.05]). In conclusion, physiological hyperinsulinemia does not affect systemic albumin permeability in healthy subjects or normoalbuminuric NIDDM patients. In contrast, in NIDDM patients, but not in healthy subjects, insulin increases the urinary excretion of albumin and protein markers of proximal tubular function. The significance of this finding for the pathogenesis of diabetic nephropathy remains to be established.

Lower extremity amputations in persons with and without diabetes in Italy: 2001-2010.

Objective To analyze hospitalization for lower extremity amputations (LEAs) and amputee rates in persons with and without diabetes in Italy. Research Design and Methods All patients with LEAs in the period 2001–2010 were identified analyzing the National Hospital Discharge Record database. For each year, amputee and hospitalization rates for LEAs were calculated either for persons with diabetes or without. Time trend for major and minor amputations were analysed. Results From 2001 to 2010 a mean annual number of 11,639 individuals underwent a lower extremity amputation: 58.6% had diabetes accounting for 60.7% of total hospitalizations. In 2010, the crude amputee rate for LEAs was 20.4 per 100,000 inhabitants: 247.2 for 100.000 persons with diabetes, and 8.6 for those without diabetes. Having diabetes was associated to an increased risk of amputation (Poisson estimated RR 10.9, 95%CI 9.4–12.8). Over the whole period, a progressive reduction of amputee rates was observed for major amputations either among persons with diabetes (−30.7%) or without diabetes (−12.5%), while the rates of minor amputations increased progressively (+22.4%) among people without diabetes and were nearly stable in people with diabetes (−4.6%). A greater number of minor amputations were performed among persons with than without diabetes: in 2010, the minor-to-major ratio among persons with diabetes (2.5) was more than twice than in those without diabetes (1.0). Conclusions The nationwide analyses confirm a progressive reduction of hospitalization and amputee rates for major LEAs, suggesting an earlier and more diffuse approach aimed at limb salvage.

Polymorphisms in the hANP (Human Atrial Natriuretic Peptide) Gene, Albuminuria, and Hypertension

Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the ScaI and BstXI polymorphisms of the human ANP (hANP) gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively (P <0.0001). Genotype distributions were in Hardy-Weinberg equilibrium in all 4 patient subgroups. The frequency of the ScaI mutated allele (A1) was significantly lower in hypertensive than in control subjects (11% versus 19%, P =0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%;P <0.0001). In a nominal logistic model adjusting for gender, age, obesity, diabetes, micro/macroalbuminuria, and hypertension, the A1 allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59;P =0.003) but not with hypertension. In the same model, the frequency of the BstXI mutated allele (T708) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59;P <0.001). We conclude that the mutated genotypes of the ScaI polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of BstXI polymorphism are positively associated with microalbuminuria. hANP gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.