Internal Medicine

Insulin Sensitivity Indices for glycemia [ISI(gly)] and blood FFA [ISI(ffa)] can be calculated with the formulas: ISI(gly) = 2/[(INSp x GLYp) + 1], and ISI(ffa) = 2/[(INSp x FFAp) + 1], where INSp, GLYp and FFAp = insulinemic, glycemic, and FFA areas during OGTT (75 g glucose) of the person under study, simplified by considering only data at 0 and 2 h (0-2 h areas), according to WHO criteria or, better, at 0, 1 and 2 h (0-1-2 h areas). Expressed as unit/volume/h, the 0-1-2 h area is equal to 1/2 value at 0 min + value at 1 h + 1/2 value at 2 h, while the 0-2 h area is equal to value at 0 min + value at 2 h. Instead of areas, basal levels can also be used. Basal levels and areas are expressed taking the mean normal value as unit, so that in normal subjects ISI(gly) and ISI(ffa) are always around 1, with maximal variations between 0 and 2. Each laboratory should have its normal reference values for basal levels and OGTT areas. However, reliable mean normal values were selected from literature. Based on meta-analysis of published data, ISI(gly) and ISI(ffa) were reduced in subjects who were overweight and/or IGT and in NIDDM patients and their relatives. Moreover, correlation of ISI(gly) with the euglycemic clamp data was significant. However, it should be stressed that the clamp procedure is performed under artificially induced steady-state whereas ISI(gly) and ISI(ffa) are obtained under rather physiological conditions, with hormonal and metabolic variables unmodified, thus being suitable to assess whole-body insulin sensitivity in the clinical setting.

In obesity several mechanisms contribute to produce insulin resistance. Elevation of plasma FFA increases the concentration of cytoplasmic long-chain-CoA (LC-CoA) and mitochondrial acetyl-CoA. The latter inhibits pyruvate dehydrogenase (PDH) and, therefore, glucose oxidation. LC-CoA exerts an array of effects, some mediated by peroxisome proliferator-activated receptors (PPARs), including modulation of gene expression of enzymes of glico-lipidic metabolism, thus inhibiting glucose utilization and potentiating FFA oxidation. On the other hand, enhanced availability of glucose plus insulin forces glucose utilization (activation of PDH and glycogen synthase) and leads to increased production of malonyl-CoA (via citrate), which inhibits carnitine-palmitoyl- transferase-1 and therefore FFA ß-oxidation. In obesity there is often enhanced availability of both FFA and glucose plus insulin. The latter condition (enhanced availability of glucose + insulin), by increasing malonyl-CoA formation, may limit FFA ß-oxidation. This, however, leads to further increase in LC-CoA, which worsens insulin resistance. All these mechanisms occur through both short-term and long-term effects. Therefore, with measurement of insulin sensitivity by the hyper-insulinemic clamp, which artificially suppresses FFA levels, the FFA short-term effects are lost. More physiological methods are those utilizing OGTT data, allowing calculation of an Insulin Sensitivity Index for glycemia, or ISI(gly), through the formula: 2/((INSp x GLYp)+1), where INSp and GLYp are the insulin and glycemic areas measured in the person under study, expressed by taking the mean normal value as 1. Corresponding Insulin Resistance Index, or IRI(gly), can be obtained through the formula: 2/((1/(INSp x GLYp))+1). Substitution of glycemic (GLYp) with FFA (FFAp) values allows the calculation of indices of insulin sensitivity and resistance for FFA, i.e. ISI(ffa) and IRI(ffa).

Serum enzymes that show changed activities in diabetes mellitus can be divided into four groups. Group I includes some lysosomal enzymes - ß-glucuronidase, N-acetyl-ß-glucosaminidase, acid phosphatase - and amylase, that show increased activity correlated with blood sugar concentration. Because lysosomal enzymes as well as liver amylase show "latency" and may be "activated" by several agents, their increased activity in the serum of diabetics might be a manifestation of an activation occurring in tissues. Group II includes alkaline phosphatase and trehalase, which are increased but not correlated with blood sugar concentration. Their enhanced activity may reflect tissue metabolic disorders. Group III includes enzymes that increase in the post-ketotic period almost regularly - phosphohexose isomerase - or in only the most severe cases - aminotransferases and several dehydrogenases - because of tissue damage caused by metabolic and circulatory alterations. Cholinesterase, on the other hand, is decreased. Group IV includes any of the above-mentioned enzymes, and still others, that may be more active in diabetics with complications such as hepatic and renal involvement and obesity.

We calculated Insulin Sensitivity Indices concerning the insulin effect on both glycemia and blood FFA, named ISI(gly) and ISI(ffa), respectively, in 34 normal, 27 obese and 11 obese-diabetic subjects by using the following formulae: ISI(gly)= 2/[(INSp x GLYp) +1], and ISI(ffa)= 2/[(INSp x FFAp)+1], where INSp, GLYp and FFAp = insulinemic, glycemic and FFA areas during OGTT (75 g glucose, suggested sampling time: 0, 1 and 2 h) of the person studied. A slight modification of these formulae allows the calculation of Insulin Resistance Indices, i.e. IRI(gly) and IRI(ffa). Sensitivity and Resistance Indices are complementary, as their sum is always equal to 2, so that IRI can be deduced from ISI and viceversa. By using basal levels, instead of areas, insulin sensitivity (or resistance) in the basal state can also be measured. Basal levels and areas are expressed by taking the mean normal value as 1, so that in normal subjects ISI(gly) and ISI(ffa), as well as IRI(gly) and IRI(ffa), are always around 1, with maximal variations comprised between 0 and 2. ISI(ffa) was markedly reduced in both the obese (mean= 0.47±0.04) and the obese-diabetic (mean= 0.41±0.06) subjects, whereas ISI(gly) was less reduced in the obese (mean= 0.57±0.04) than in the obese-diabetic (mean= 0.40±0.03) subjects. ISI(gly)-basal was less affected than ISI(ffa)-basal in both groups. Multiple regression showed that ISI(gly) and ISI(ffa) were significantly correlated with age, BMI and diastolic (but not systolic) blood pressure. Meta-analysis of data from the literature showed that ISI(gly) was significantly correlated with the hyperinsulinemic-euglycemic clamp data. However, the "clamp" is performed under artificial, persistent hyperinsulinemia (which entails FFA suppression) as never occurs in the life of patients, whereas our indices are performed under physiological conditions, and represent simple tools, suitable for clinical or epidemiological studies, allowing assessment of whole-body insulin sensitivity with regard to both glycemia and blood FFA.

In each of 10 highly hyperglycemic decompensated diabetic patients with ketoacidosis, we found a markedly increased serum activity of two lysosomal hydrolases (N-acetyl-ß-glucosaminidase and ß-glucuronidase). This was also true, to a lesser degree, of five diabetics with less severe decompensation and without ketoacidosis. The activity of both enzymes and the degree of hyperglycemia were highly correlated. We think these enzymatic changes result from a process of activation and release of tissue lysosomal enzymes, probably occurring in connection with the increased catabolism present in decompensated diabetes. Non-lysosomal (cytoplasmic or mitochondrial) enzymes were less changed (aspartate and alanine aminotransferases) or normal (aldolase, lactate- and malate-dehydrogenase, and creatine kinase). This indicates that tissue damage alone could not account for the increased activity of the two lysosomal hydrolases; it therefore seems primarily to be due to involvement of lysosomes.

In the sera of patients with diabetic coma (n=14), amylase activity was markedly elevated, compared to normal subjects (n=60), and closely correlated with the activity of some lysosomal enzymes, including ß-glucuronidase, N-acetyl-ß-glucosaminidase and acid phosphatase. All these enzyme activities returned to normal with the normalization of glycemia. Activities of serum lipase, aspartate and alanine aminotransferases, aldolase, and lactate dehydrogenase were not changed. Since liver amylase, although primarily contained in microsomes, shows latency and is activated by several agents as are lysosomal enzymes, these findings might be regarded as a further evidence of a similarity between amylase and lysosomal enzymes, and make probable the hypothesis that a process of activation occurring in liver might be the cause of the increase of serum amylase activity as well as of lysosomal enzymes.

In 45 diabetics the 24-h urinary excretion of ß-N-acetyl-glucosaminidase (E.C. 3.2.1.30) was increased by 40% (P<0.05) compared to 35 control subjects. The enzyme excretion was correlated with glycemia (r= 0.58, P<0.001), being little changed in diabetics with blood glucose concentrations of less than 200 mg/dL, and markedly elevated (+123%, P<0.001) in those whose blood glucose was greater than 200 mg/dL. The rate of diuresis seemed to have no effect. These data indicate that the enhanced activity previously described in sera of diabetics for ß-N-acetyl-glucosaminidase (as well as for other lysosomal enzymes) cannot be attributed to impairment of renal excretion, and support the hypothesis that in diabetes there is an "activation" of lysosomal enzymes in tissues that causes an increase in their activity in serum and, consequently, in urine.

Insulin, glucagon, glucose, nonesterified fatty acids (NEFA), and lactate response to oral glucose tolerance test (OGTT, 75 g glucose) and their correlation with mean blood pressure (BP), were studied in 10 normal subjects (N), 25 subjects with abdominal obesity (O), and 9 subjects with abdominal obesity and IGT or non-insulin-dependent diabetes (OD). O and OD patients, as compared to N subjects, showed increased fasting NEFA, lactate, insulin, and glucagon. NEFA area and insulin total and incremental areas were increased in O and OD (P<0.001 in all instances). Glucagon total area was increased only in OD (P<0.01). Lactate total area was increased in O (P<0.001) and in OD (P<0.01), while lactate incremental area was diminished in O and, even more, in OD subjects (P<0.001 in both instances) and was inversely correlated with the basal level (P<0.001). In all subjects as a whole, increase in NEFA area was weakly correlated with total and incremental insulinemic areas (P<0.05) and more strongly correlated with glucagon and lactate areas (P<0.01). Conversely, the incremental area of lactate was negatively correlated with total insulin (P<0.05), NEFA (P<0.05), and glucagon (P<0.001) areas. BP was increased in O (103.62 ± 2.37) and, even more, in OD (109.41 ± 5.22) compared to N (92.55 ± 0.94 mm Hg), with P<0.01, and was correlated with fasting insulin (P<0.01) and glucose (P<0.05) and, even more, with total (P<0.001) and incremental (P<0.01) insulin areas and NEFA area (P<0.001). Conversely, BP was negatively correlated with incremental lactate area (P<0.01) (similarly to insulin and NEFA area). Our data would suggest that in O and OD patients, insulin resistance is associated with elevated NEFA, insulin and glucagon as well as with high BP. Since NEFA are inhibitors of Na,K-ATPase, they could contribute to elevate BP through the repression of this enzyme (which we have shown previously to be reduced in adipose tissue of obese subjects and correlated negatively with BP).

In a group of ten adult obese subjects, maintained for 15 days on a normal caloric intake and balanced diet, the activity of hexokinase (EC 2.7.1.1), 6-phosphofructokinase (EC 2.7.1.11), and ATP citrate-lyase (EC 4.1.3.8) in the adipose tissue was significantly increased, both on a protein and on a fat cell number basis, compared to matched normal subjects. The activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), malate dehydrogenase (EC 1.1.1.37), and malate dehydrogenase (decarboxylating) (NADP) (EC 1.1.1.40), on the other hand, was unchanged. Since both hexokinase and 6-phosphofructokinase are rate-limiting in glycolysis, their enhanced activity would indicate the occurrence of an increased capacity to metabolize glucose and therefore to generate alpha-glycerophosphate. The elevation of ATP citrate-lyase would suggest increased lipogenesis, owing to the regulatory role that this enzyme plays in fatty acid synthesis. The normal activity of glucose-6-phosphate dehydrogenase and malate dehydrogenase (decarboxylating) (NADP), which supply NADPH for the reduction of acetyl-CoA to fatty acids, would suggest that the change in lipogenesis is of moderate degree, thereby affecting only the most rate-limiting enzyme, ATP citrate-lyase. These data, on the whole, are consistent with the occurrence of enhanced triglyceride formation. Whether the enzyme changes observed are adaptive or genetic in nature remains to be clarified.

In this book, the author attempts to explain the nature of human society and to provide a justification of the democratic system, often charged with favoring numerousness over quality. Starting from his conception of the structure and functioning of human mind, previously published, Belfiore derives a set of democratic principles that allow to conceive society as the necessary result of the trend of human actions and moral acts toward universalization, and the democratic system (based on majority rule and universal suffrage) as the only one through which actions and moral acts can reach the best possible approach to universality. Since evolution toward universality is regarded as part of mind evolution, which in turn is conceived as the objective good, democratic society is given an objective ontological and moral foundation. Likewise, the author provides new insights and offer novel solutions for many issues concerned with the complex functioning of the democratic society, such as: the nature of political parties, the political positions known as Right and Left, the duality of the forces that drive political activity (egoism/right/freedom versus morality/duties/equality), the voting system, the justification of majority rule, the role of leaders and elected representatives, voters’ preferences, political choices, the unity-distinction of the three powers of the State, and still others. Belfiore contrasts his views with those of other thinkers, who are extensively quoted. The result is an original and exhaustive text, which will be useful for a better understanding of the democratic society.

The revised edition of The Ontological Foundation of Ethics, Politics, and Law (1st ed. 2007) adds new concepts and discusses the views of additional thinkers. The author refers to his basic ontological conception of the human “mind” or “spirit” as an evolving, conscious, triadic entity composed of intellect, sensitivity, and power, each exerting a bidirectional (selfish and moral) activity. Through this approach, the notions of good, morality, society, and law are derived from the structure and functioning of the mind. It follows that the solutions presented are the results of a discovery and not the consequence of a choice. Otherwise stated, ethics, politics, and law are given an ontological foundation. For each topic considered, Belfiore shows how his thought can reinterpret the views of other philosophers. This new edition, enriched in concepts and quotations, appears as an innovative and highly stimulating contribution to the philosophical branches of ethics, politics, and law, and will be of interest to both graduate students and philosophy scholars.

This short book describes the negative effects exerted by Catholicism on the large majority of Catholics. It is critically focused on such issues as: papal infallibility; believing in miracles; the imposition of rules that cannot be followed (condemn of any sexual act not directed to procreation); easy forgiveness; the exclusion of women; the cult of Saints as “protectors”; the ostentation of power and richness; the pursuing of pseudo-values, such as chastity; the undue interference in the sphere of politics. In the two final chapters, a general comment is given.

In The Triadic Structure of the Mind, Francesco Belfiore begins from the basic ontological conception of the structure and functioning of the “mind” or “spirit” as an evolving, conscious triad composed of intellect, sensitiveness, and power, each exerting a selfish or moral activity. Based on this concept, Belfiore has developed a coherent philosophical system, through which he offers fresh solutions in the fields of ontology, knowledge, language, aesthetic, ethics, politics, and law. The second edition of the book includes a more extensive treatment of the topics addressed in the first edition, the introduction of new concepts, and the inclusion of additional thinkers, whose views have been discussed and reinterpreted.