Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications.

AIMS: Improvements in diagnostic methods and greater genetic awareness have brought remarkable progress in the recognition of monogenic forms of diabetes, including Wolfram syndrome (WFS). WFS is diagnosed based on clinical criteria of coexistence of diabetes mellitus and optic atrophy, and confirmed by molecular analysis; however, the condition is still sometimes misdiagnosed. To begin to understand the reasons for misdiagnosis, we conducted a retrospective analysis of WFS patients who were originally misdiagnosed. MATERIALS AND METHODS: The medical histories of 13 pediatric patients with clinical misdiagnosis of type 1 diabetes and early chronic complications made in the years 1995-2010 and who were subsequently correctly diagnosed with WFS based on genetic testing in 2008-2011 were analyzed. RESULTS: The average age of the patients at diabetes onset was 5 (4.4-6.3) years, and the mean HbA1c level at diagnosis was 9.1±2.3%. Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5±1.3%). Diagnosis of optic atrophy was made at an average age of 9 (5.9-11.5) years, which corresponds to 4 years after diabetes recognition (p=0.002). At the time of genetic analysis, the average age of the patients was 16 (12-18.7) years, which corresponds to 7 years after recognition of coexistence of diabetes mellitus and optic atrophy (p=0.007). CONCLUSIONS: Delays of at least 7 years occurred before recognition of WFS among a cohort of pediatric patients with diabetes. All patients with WFS were primarily misdiagnosed as having type 1 diabetes.

Women with normal glucose tolerance and a history of gestational diabetes show significant impairment of ß-cell function at normal insulin sensitivity.

OBJECTIVE: Although the nature of gestational diabetes mellitus (GDM) remains unclear, the condition is thought to be related primarily to insulin resistance, overweight and obesity. Most studies include women with a history of GDM and later carbohydrate metabolism abnormalities, while reports of women with previous GDM and subsequent normoglycaemia are scarce. The aim of this study was to assess insulin resistance and ß-cell function in normoglycaemic women with a history of GDM. MATERIALS AND METHODS: The study group included 199 women, aged 38.4±6.6 years, diagnosed with GDM within the last 5-12 years [GDM(+)] and a control group of 50 comparable women in whom GDM was excluded [GDM(-)], according to WHO criteria. Blood glucose and insulin levels were measured at the beginning (fasting) and at 60 and 120min of oral glucose tolerance tests. Indices of insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S%) and ß-cell function (HOMA-B%) were calculated. RESULTS: Normoglycaemia was observed in 57% of GDM(+) and 88% of GDM(-) women (P=0.0003). Diabetes was diagnosed in 13 (6.5%) GDM(+) women and in none of the GDM(-) women. Comparison of 113 normoglycaemic GDM(+) and 44 normoglycaemic GDM(-) women revealed significantly impaired ß-cell function (HOMA-B%: 131.1±51.1 vs 144.7±47.1, respectively; P=0.038) with similar normal body mass index (BMI) and no differences in HOMA-IR and HOMA-S%. CONCLUSION: In this study, more than half of the GDM(+) women were presented with normal glucose tolerance. However, despite normoglycaemia, women with a history of GDM were characterized by significantly impaired insulin secretion, but no signs of increased insulin resistance.

The common C49620T polymorphism in the sulfonylurea receptor gene (ABCC8), pancreatic beta cell function and long-term diabetic complications in obese patients with long-lasting type 2 diabetes mellitus.

HYPOTHESIS: A gene polymorphism associated with accelerated beta-cell failure may lead to a more rapid development of long-term complications of type 2 diabetes (T2DM) due to a worse metabolic control of the disease. AIM OF THE STUDY: Evaluation of an association between the intronic C49620T (exon 16 -3c-->t) polymorphism in the ABCC8 (SUR1) gene and beta-cell function, as well as the prevalence of long-term diabetic complications in obese patients with long-lasting type 2 diabetes. METHODS: Two hundred and fifteen obese patients with at least a 10-year history of T2DM were thoroughly characterized clinically. In all the patients the intravenous glucagon test was performed and the C49620T ABCC8 polymorphism was assessed. Subgroups of patients, classified either according to genotype or to allele carriage, were compared. RESULTS: No difference was found between the groups in variables describing beta-cell function and the prevalence of chronic diabetic complications, with the exception of a significantly lower incidence of brain stroke in CC homozygotes than in patients carrying T allele (CT+TT). Body mass index was higher in patients carrying C allele than in TT homozygotes. HDL-cholesterol was higher in CT heterozygous than in homozygous CC or TT patients. CONCLUSIONS: There is no association between the ABCC8 polymorphism gene and the beta-cell function or the prevalence of chronic diabetic complications in obese patients with long-term T2DM, except for brain stroke. The results might suggest that the homozygous CC subjects are at lower risk of the complication, but additional studies are warranted to test this finding.

Association between the Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma2 gene and increased 24-h diastolic blood pressure in obese patients with type II diabetes.

The aim of the study was to examine an association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma2 gene and blood pressure values assessed by 24-h ambulatory blood pressure monitoring (ABPM) in obese patients with long-lasting type II diabetes. Two hundred and fourteen obese patients (95 men and 119 women) with above 10-year history of type II diabetes were recruited for the study. In all the patients, ABPM was performed and other parameters, including age, body mass index (BMI), waist/hip ratio (WHR), haemoglobin A1c (HbA(1c)), serum lipids and creatinine were also evaluated. The Pro12Ala polymorphism was analysed by polymerase chain reaction-restriction fragment length polymorphism. Two subgroups of patients were compared: (a) Pro/Pro: homozygotic Pro/Pro (n=154) and (b) Ala: Ala allele carriers (Ala/Ala+Ala/Pro) (n=60). The studied groups were not different when age, BMI, WHR, HbA(1c), lipids, creatinine and frequency of hypertension were compared. A similar ratio of patients from both groups were treated with angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, beta-blockers and alpha-blockers. A difference was observed in a mean 24-h (Ala: 71.9+/-8.1 vs Pro/Pro: 69.4+/-7.8 mm Hg, P=0.034) and a mean night time (Ala: 67.1+/-7.8 vs Pro/Pro: 64.5+/-8.4 mm Hg, P=0.025) diastolic blood pressure, which was significantly higher in patients with Ala variant. There was also a trend towards a higher mean daytime diastolic blood pressure in this group. It seems that the Pro12Ala variant is associated with an increased mean 24-h diastolic blood pressure in obese diabetic patients. Different reaction for antihypertensive medication depending on a variant of the PPAR-gamma2 gene should also be considered as a possible cause of the presented results.

[Tests for evaluating insulin sensitivity in vivo]. / Testy oceniajace wrazliwosc tkanek na insuline in vivo.

Insulin resistance is a characteristic feature of different physiological states including puberty, pregnancy, elderly and is associated with numerous common medical disorders as obesity, diabetes mellitus type 2, hyperlipidaemia, essential hypertension. Tests used for estimation of insulin sensitivity in vivo can be divided into indirect tests measuring action of endogenous insulin, usually in response to a glucose stimulus, and direct tests measuring glucose metabolism in response to exogenous insulin. Indirect tests--oral glucose tolerance test, intravenous glucose tolerance test, minimal Bergmans method, continuous infusion of glucose with model assessment (CIGMA), hyperglycemic clamp and direct tests--intravenous insulin tolerance test, insulin suppression test, euglycemic clamp are described, and their advantages and disadvantages are discussed.

[Elevated plasma prekallikrein level in patients with diabetes]. / Podwyzszony poziom prekalikreiny osoczowej u chorych na cukrzyce.

The contact activation of intrinsic pathway in the coagulation system accompanied by plasma kallikrein-induced kinin generation is thought to be involved in the pathogenesis of diabetic retinopathy. Plasma prekallikrein (PPK), a proenzyme of plasma kallikrein, is a single-chain glycoprotein synthesized mainly in the liver. The aim of our study was to evaluate plasma prekallikrein level in diabetic patients and to examine the relationship between PPK and the metabolic control of diabetes and development of retinopathy. In 53 diabetic patients and 33 healthy subjects as controls the following parameters have been assessed: plasma prekallikrein, serum fructosamine, glycated haemoglobin HbA1c, prothrombin time, partial thromboplastin time and antithrombin III (AT III). Compared to the control group, PPK level was significantly higher in diabetics, especially in patients with proliferative retinopathy. The significant positive correlations have been found between PPK and HbA1c in diabetic patients and between PPK and serum fructosamine concentration but only in diabetics without retinopathy. No differences in prothrombin time and AT III have been observed between diabetics and healthy subjects. A suggestion is presented on increase of plasma prekallikrein level in diabetics due to hyperglycaemia-stimulated glycoprotein over-synthesis in the liver, what would confirm the role of kallikrein-kinin system in the pathogenesis of microangiopathy.

[Selected parameters of blood coagulation and fibrinolysis and their relationship to the level of diabetes control in patients with insulin-dependent diabetes mellitus]. / Wybrane parametry ukadu krzepniecia i fibrynolizy oraz ocena ich zaleznosci od stopnia wyrównania cukrzycy u chorych na cukrzyce insulinozalezna.

The aim of the study was to evaluate plasma concentration of fibrinogen, plasma activity of antithrombin III (AT-III) and plasma activity of plasminogen activator inhibitor (PAI-I) in insulin-dependent diabetic (IDDM) patients and the assessment of correlation between them and the parameters of glyco-metabolic control comprising glycemia and concentrations of fructosamine and glycated hemoglobin HbA1c. Eighteen IDDM patients (mean age 28.3 +/- 11.3 ys, mean duration of disease 12.2 +/- 5.3 ys) without over nephropathy and without macroangiopathy were investigated. Control group consisted of 8 healthy subjects. Plasma fibrinogen concentrations were similar in IDDM patients and in controls (3.54 +/- 0.45 g/l and 3.31 +/- 0.54 g/l respectively). Plasma activity of AT-III in diabetic patients (90.6 +/- 22.4%) was similar to that in healthy subjects (94.6 +/- 25.0%). Fibrinogen concentrations and AT-III activities showed no correlation with glycemia and concentrations of fructosamine and HbA1c. Plasma activity of PAI-I was significantly lower in diabetics than in controls (respectively 1.56 +/- 0.72 U/ml and 2.75 +/- 1.25 U/ml, p < 0.005). PAI-I activity correlated negatively with fasting blood glucose (p < 0.05) but did not correlate with concentrations of fructosamine or HbA1c. The results suggest that glycemic control in diabetic patients do not influence on concentrations of fibrinogen and activity of AT-III but diminished activity of PAI-I is related to hyperglycemia.

[Effect of treatment of arterial hypertension on renal function in patients with imminent and overt diabetic nephropathy]. / Wplyw efektywnego leczenia nadcisnienia tetniczego na czynnosc nerek u chorych z zagrazajaca i jawna nefropatia cukrzycowa.

The effect was studied of blood pressure lowering treatment on renal failure and albuminuria (UAE) in patients with type I diabetes (IDDM) and imminent nephropathy as well as in patients with over diabetic nephropathy. The group of 24 patients with imminent nephropathy was subdivided: 1. twelve patients with borderline or overt hypertension with mean BP lowered not below 100 mmHg, and 2. twelve patients with BP within the normal limits, taking no hypotensive agents. In the other group of 12 patients with overt diabetic nephropathy hypertension was lowered below 105 mmHg and kept so for at least two years. All patients estimated their glycemia and glycosuria by themselves, ate 0.8 g protein/kg/24 h and about 100 mmol Na/24h. Under hospital conditions the following were estimated: albuminuria, glomerular filtration rate (51Cr EDTA) and effective renal blood flow (131I hippurate). The same examinations were repeated 1 year and 2 years later. The lowering of BP below 100 mmHg in patients with imminent diabetic nephropathy significantly lowered microalbuminuria without changing GFR, ERPF despite good or satisfactory compensation of diabetes. Maintaining BP below 105 mmHg for 2 years did not prevent the patients with overt nephropathy to develop progressive renal failure despite the rate of GFR deterioration and of the increase of albuminuria slowed down.

[Alport's syndrome in twins]. / Zespól Alporta u blizniaków.

Alport's syndrome consists of hereditary nephritis, often progressing to renal failure, and variable neural hearing loss. It was diagnosed in dizygotic twins, aged 32 years, suffering from nephropathy manifested by microscopic hematuria, proteinuria and chronic renal failure, accompanied by hearing loss and ocular disorders (observed in both retina and lenses). Gothic palate has been noted in both patients. Glomerulitis was diagnosed for the first time at the age of 11 and 12 years, respectively. Hearing loss began in one brother 10 years later, and in another 11 years later. Renal failure developed much later. Diagnostic problems were due to the fact, that streptomycin was used in childhood (another cause of hearing loss?) and to the lack of any symptoms of Alport's syndrome in other members of the family.

[Cytoplasmic islet-cell antibodies (ICA) and cytoplasmic complement- fixing antibodies (CF-ICA) in patients with newly detected and short-lasting diabetes mellitus type 1]. / Przeciwciala przeciwwyspowe cytoplazmatyczne ICA i cytoplazmatyczne wiazace dopelniacz CF-ICA u chorych na swiezo rozpoznana i krótko trwajaca cukrzyce typu I.

The study aimed at assessing ICA and CF-ICA in the serum of patients with newly diagnosed and short-lasting diabetes mellitus type 1. Sixty patients with newly diagnosed diabetes type 1 (39 patients) and short-lasting diabetes of the same type (21 patients) aged between 2 and 34 years were classified. Anti-islet antibodies were detected with indirect immunoflourescence in specimens of fresh, frozen human pancreast in the tested group ICA were found in 53% of cases. At the time of diagnosis, ICA were found in 76% of children and in 14% of adult patients whereas respective data for diabetes mellitus lasting up to 2 years were 40% and 64%. Complement-fixing islet cytoplasmatic antibodies were found only in patients with ICA (47% of such cases). These antibodies were found in children with newly diagnosed diabetes mellitus (36%). In case of adults CF-ICA were detected in 7% of newly diagnosed diabetes mellitus cases and in 45% of cases with the disease lasting for 2 years. Titres of ICA ranged from 1:1 to 1:128 whereas titres CF-ICA from 1:1 to 1:8. No correlation between ICA titre and CF-ICA titre was noted.

[Islet cell cytoplasmic antibodies (ICA) and complement-fixing islet cell cytoplasmic antibodies (CF-ICA) in patients with newly detected type 1 diabetes mellitus of short duration]. / Wystepowanie przeciwcial przeciwwyspowych cytoplazmatycznych ICA i cytoplazmatycznych wiazacych dopelniacz CF-ICA u chorych ze swiezo rozpozana i krótko trwajaca cukrzyca typu I.

Cytoplasmic islet cell antibodies and endogenous insulin secretion were studied in 60 children and adolescents having insulindependent (Type I) diabetes mellitus. The age of the subjects was 2-34 years. Thirty-nine patients were investigated at the time of diagnosis, in the group of 21 patients duration of disease was shorter than 2 years. Islet cell antibodies were analysed by indirect immunofluorescence for both conventional (ICA) and complement-fixing (CF-ICA) antibodies using cryostat sections of fresh frozen human pancreas. ICA were observed in 53% of patients. At the time of diagnosis 76% of children and 14% of adults were positive for ICA. In the remaining group of patients ICA were observed in 40% of children and 64% of adults. CF-ICA were present only in the ICA positive sera (47%). ICA titres were 1:1-1:128, CF-ICA titres were 1:1-1:8. There was no linkage between ICA and CF-ICA titres. The residual beta cell function was measured by serum C-peptide. There was no association between presence of ICA and residual beta cell function. The patients having CF-ICA had a significantly higher endogenous insulin secretion in comparison with the patients who were ICA negative.