Etiology, diagnosis, and prevention of renal involvement in insulin-dependent diabetes mellitus

Overt diabetic nephropathy is a well-established clinical picture characterized by macroproteinuria and irreversible decline of glomerular function. The first phase of renal involvement has been widely investigated in the last decade in the hope to individuate early lesions. Five stages of glomerular damage have been identified by morphological abnormalities and clinical tests. Although renal hypertrophy, hyperfiltration, and microalbuminuria are present in all diabetics at onset, subsequent evolution shows different patterns: some patients may present no further progression, while others show a rapid and irreversible decline of kidney function. This suggests that other factors, i.e., risk factors, may play important roles in the renal involvement in diabetics. The predictive role of microalbuminuria and of hyperfiltration was investigated, and, so far, only an albumin excretion rate above 30 micrograms/min had been proved to be associated with a decline of renal function. Actually no practical hints can be given to prevent the disease apart from persistent strict glycometabolic control during the course of diabetes. Antihypertensive treatment can slow glomerular damage when overt diabetic nephropathy and hypertension are present. Aggressive treatment in the early phases of renal involvement might change the natural history of the disease.     

Blood sugar response to administration of bran or guar added to pasta in children with type I diabetes

Blood sugar profiles after administration of pasta with (PG) and without (P) guar have been evaluated in 30 young type I diabetic children. Maximum increase of blood sugar was observed at 30' (mean = 21 mg/dl) after P and at 90' (mean = 6 mg/dl) after PG. Maximum decrease in blood sugar levels was reached at 180' in both groups (50 mg/dl after P and 25 mg/dl after PG). Blood sugar level was significantly different only at 180'. No significant difference was observed analyzing rates of increase.     

Frequency and correlates of severe hypoglycaemia in children and adolescents with diabetes mellitus

Frequency and correlates of severe hypoglycaemia have been retrospectively analysed in a cohort of diabetic children and adolescents with median (range) age 14.5 (3.2–25.5) years followed from the onset of the disease by the same diabetic clinic. During the years 1992–1994, 53 of the 187 patients reported 74 hypoglycaemic episodes: the average frequency of hypoglycaemia during the 3 years surveyed was 14.9 episodes/100 patients per year. Frequency of hypoglycaemia decreased significantly with age (χ² = 24.1; P < 0.0001) and was independent of duration of diabetes. Glycosylated haemoglobin and insulin dose were similar in patients with and without hypoglycaemia, matched for age and duration of diabetes. One out of two hypoglycaemic episodes occurred during sleep and no explanation was available for 50% of episodes. Conclusion In this study severe hypoglycaemia was more frequent in young children than in adolescents and was independent of metabolic control and insulin dose. Received: 25 May 1996 / Accepted: 3 February 1997     

The prevalence of antibodies to human herpesvirus 8 and hepatitis B virus in patients in two hospitals in Tanzania

The aim of this study was to determine the seroprevalence of human herpesvirus 8 (HHV‐8) and the immunization status for hepatitis B virus (HBV) infection in febrile patients in two districts of the United Republic of Tanzania. Between February and March 2007, blood samples were collected in Pemba Island and Tosamaganga from 336 outpatients and sent to the Virology Laboratory in Rome (Italy) for testing. HHV‐8 DNA and HBV‐DNA were amplified by two in‐house molecular methods, anti‐HHV‐8 antibody titers were determined by an immunofluorescence assay (IFA), and anti‐HCV, HBsAg, anti‐HBs, and anti‐HBc were evaluated by microplate enzyme immunoassay (MEIA). The seroprevalence of HHV‐8 was 30.7% (96/313). In Pemba Island, the prevalence was lower than in Tosamaganga (14.4% vs. 46.3%). A higher prevalence of low titers of HHV‐8 IgG (<1:80, 81%) was found among those under 5 years of age. HHV‐8 DNA was detected in six seropositive patients (6.7%). The prevalence of HBsAg, anti‐HBs, and anti‐HBc was 4.3%, 37.6%, and 29.3%, respectively. Out of 277 patients, 70 had had a previous infection (25.3%). One case of occult hepatitis was found. The cover of hepatitis B vaccination was higher among children born after 2002 (66.7%) than in patients born before 2002. HHV‐8 infection is endemic in Tanzania and the seroprevalence rate was higher in the mainland than on Pemba Island. The 3.9% percentage of HBsAg in children younger than 4 years of age suggests that increased efforts are required in order to achieve universal and compulsory immunization of children against HBV. J. Med. Virol. 82:1569–1575, 2010. © 2010 Wiley‐Liss, Inc.     

Maturity-Onset Diabetes of the Young in Children With Incidental Hyperglycemia:: A multicenter Italian study of 172 families

OBJECTIVE

To investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia.

RESEARCH DESIGN AND METHODS

Among 748 subjects age 1–18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes were performed.

RESULTS

We identified 85 GCK gene mutations in 109 probands and 10 HNF1Α mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients.

CONCLUSIONS

GCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia.Between 1992–1999, the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) Study Group on childhood pre-diabetes recruited 748 individuals with incidental hyperglycemia to be screened for markers of type 1 diabetes (1,2). Among autoantibody-negative subjects, a significant number (∼23%) met the criteria for clinical diagnosis of maturity-onset diabetes of the young (MODY), i.e., two or three consecutive generations with hyperglycemia diagnosed before age 25 years (3,4). Alterations in at least six different genes cause MODY (3), with mutations of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes accounting for up to 85% of MODY in Europe. Defects of other MODY genes are quite rare (3). The aim of this study was to screen for GCK and HNF1Α genes in 172 Italian children with incidental hyperglycemia and clinical diagnosis of MODY.     

Insulin gene mutations as cause of diabetes in children negative for five type 1 diabetes autoantibodies

OBJECTIVE—Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies.RESEARCH DESIGN AND METHODS—We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients.RESULTS—In two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age, respectively, we identified the mutation G^B8S and a novel mutation in the preproinsulin signal peptide (A^Signal23S).CONCLUSIONS—Insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes autoantibodies.Mutations of the insulin (INS) gene associated with neonatal- and infancy-onset diabetes cause sustained stress of the endoplasmic reticulum, which in turn triggers apoptosis of the pancreatic β-cell (1). In patients with insulin mutations with proteotoxic effect, diabetes presents in isolation and the onset of hyperglycemia may occur well outside the neonatal period (1–4). As a consequence, individuals with INS gene mutations may be confused with patients having autoimmune type 1 diabetes (1–4).     

T cell responses to type 1 diabetes related peptides sharing homologous regions

Glutamic acid decarboxylase (GAD) 65 is a major autoantigen in type 1 diabetes. Regions of homology exist between GAD65 (residues 250-273) and the Coxsackie P2-C protein (residues 28-50) and between GAD65 (residues 506-518) and proinsulin (residues 24-36), and each of these has been reported to be a diabetes-associated T cell target. The aim of this study was to determine whether the homologous regions are shared targets of T lymphocyte reactivity in individual patients with type 1 diabetes. T cell proliferation against the corresponding peptide pairs, GAD254-276 and Coxsackie P2-C32-54 and GAD506-518 and proinsulin24-36, were measured in peripheral blood mononuclear cells from 26 patients with newly diagnosed type 1 diabetes and 24 control subjects. Responses with stimulation indices higher than 3 were found against each of the antigens tested in both patients and control subjects, and no differences were observed between groups. A strong positive correlation was found between responses to the corresponding peptide pairs GAD254-276 and Coxsackie P2-C32-54 (r=0.77, P<0.0001), and between responses to the corresponding peptide pairs GAD506-518 and proinsulin24-36 (r=0.66, P<0.0001). However, a similar correlation was also observed between responses to the noncorresponding pairs Coxsackie P2-C32-54 and proinsulin24-36 (r=0.82, P<0.0001), Coxsackie P2-C32-54 and GAD506-518 (r=0.82, P<0.0001), and GAD254-276 and proinsulin24-36 (r=0.83, P<0.0001). Strikingly, increased responses to peptides were found almost exclusively in subjects with high stimulation indices against the recall antigen tetanus toxoid, further suggesting that peripheral blood T cell responses are related to a general subject hyperreactivity. These data suggest that proliferative T cell responses to peptides containing putative autoreactive epitopes of GAD65 and proinsulin are not specific for type 1 diabetes, that correlation between T cell reactivity to peptides is not restricted to those containing homologous regions, and that non-antigen-specific factors are important determinants of in vitro measurements of T cell reactivity.     

Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?

Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson–Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter’s syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.     

Differential Dynamics of SARS-CoV-2 Binding and Functional Antibodies upon BNT162b2 Vaccine: A 6-Month Follow-Up

To investigate the dynamic association among binding and functional antibodies in health-care-workers receiving two doses of BNT162b2 mRNA COVID-19-vaccine, SARS-CoV-2 anti-RBD IgG, anti-Trimeric-S IgG, and neutralizing antibodies (Nabs) were measured in serum samples collected at 2 weeks, 3 months, and 6 months from full vaccination. Despite the high correlation, results for anti-RBD and anti-Trimeric S IgG were numerically different even after recalculation to BAU/mL following WHO standards indications. Moreover, after a peak response at 2 weeks, anti-RBD IgG levels showed a 4.5 and 13 fold decrease at 3 and 6 months, respectively, while the anti-Trimeric S IgG presented a less pronounced decay of 2.8 and 4.7 fold. Further different dynamics were observed for Nabs titers, resulting comparable at 3 and 6 months from vaccination. We also demonstrated that at NAbs titers ≥40, the area under the receiver operating characteristic curve and the optimal cutoff point decreased with time from vaccination for both anti-RBD and anti-Trimeric S IgG. The mutating relation among the anti-RBD IgG, anti-Trimeric S IgG, and neutralizing antibodies are indicative of antibody maturation upon vaccination. The lack of standardized laboratory procedures is one factor interfering with the definition of a correlate of protection from COVID-19.