Maternally inherited diabetes with deafness and obesity: body weight reduction response to treatment with insulin analogues.

Maternally inherited diabetes with deafness (MIDD) is a rare, monogenic form of diabetes mellitus caused by mutations in the mitochondrial genome, the most frequent being the A3243G substitution of the tRNA(Leu) gene. We screened 520 individuals with type 2 diabetes mellitus and 45 probands from families with a clinical picture of maturity onset diabetes of the young (MODY) using restriction fragment length polymorphism. One carrier of the mutation being investigated was found in a proband from a MODY family. The patient was a 20 year-old woman, diagnosed at the age of 16 years as having type 1 diabetes mellitus. On entry to the study, she was treated by a multiple daily injection regimen (MDI) with regular human insulin and human NPH insulin. Typical extra-pancreatic symptoms of MIDD were present, such as macular pattern dystrophy and mild bilateral sensory hearing loss. Additionally, the patient presented abdominal obesity (BMI 32.0), an uncommon feature in monogenic insulin secretion defects, including MIDD. To facilitate weight loss, the diabetes treatment was modified. Since metformin treatment is considered to be contraindicated in MIDD because of the increased risk of lactic acidosis, we used insulin analogues (aspart and detemir) in an MDI regimen and hypocaloric diet. This resulted in a 6.3 kg weight reduction (BMI 27.4) and normalization of HbA1c level (from 7.2 to 6.1 %) during a three-month follow-up. On the basis of this case, we suggest that an MDI regimen with insulin analogues may be a preferred therapeutic option in some rare clinical situations, such as MIDD associated with obesity.

Family history of end-stage renal disease among hemodialyzed patients in Poland.

BACKGROUND: In previous reports of end-stage renal disease (ESRD) patients, family history of ESRD was associated with race, younger age, higher education levels and ESRD etiology. This study aimed to analyze how often Polish caucasian dialysis patients reported relatives with ESRD, and to evaluate which risk factors are associated with family history of ESRD. METHODS: 4808 ESRD patients provided data about renal disease etiology, diabetes and hypertensive status of first- and second-degree relatives, socioeconomic status and education level. RESULTS: Reported ESRD etiologies were: chronic glomerular disease, 19.4 %; diabetic nephropathy, 11.3%; interstitial nephritris, 11.2%; hypertension, 7.8%; polycystic kidney disease (PKD), 7.1%; other or no response, 40.0%. Positive ESRD family history was reported by 745 patients (15.5%); positive history of diabetes, 932 (19.4%); hypertension, 1904 (39%). Positive ESRD family history according to kidney disease etiology was: PKD, 53.1%; glomerulonephritis, 12%; diabetic nephropathy, 11.9%; hypertension, 11.8%; interstitial nephritis, 10.8%. PKD as ESRD etiology (odds ratio (OR) 8.06, 95% confidence interval (CI) 6.35-10.23, p < 0.0001), positive family history of diabetes (OR 1.64, 95% CI 1.34-1.99, p < 0.0001) and positive history of hypertension (OR 1.64, 95% CI 1.39-1.95, p < 0.0001), were independently associated with positive ESRD history. Patients with later ESRD onset had a less frequent positive ESRD family history: for ESRD < 45 yrs, 16% (OR 1.0); 45-64 yrs, 14.4% (OR 0.83, 95% CI 0.70-0.99); > or = 65 yrs, 9.2 % (OR 0.5, 95% CI 0.35-0.72). CONCLUSIONS: Results of our study strongly support the contention that familial predisposition contributes to ESRD development.

Methylenetetrahydrofolate reductase gene polymorphism and susceptibility to diabetic nephropathy in type 1 diabetes.

BACKGROUND: The T allele of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated plasma homocysteine levels, and it has been postulated to be a risk factor for the development of diabetic nephropathy. We examined this hypothesis in both a case-control and a follow-up study in individuals with type 1 diabetes. METHODS: In the case-control study, the control group included 310 subjects with normoalbuminuria and diabetes duration of 15 years or greater, and the case group included 88 prevalent cases with end-stage renal disease (ESRD). The follow-up study included 235 subjects with overt proteinuria followed up for 6 years (on average), during which time ESRD developed in 69 subjects. DNA from each individual was genotyped for the C677T MTHFR polymorphism. RESULTS: The frequency of TT homozygotes did not vary significantly among the four groups: 10% in controls, 15% in prevalent cases of ESRD, 13% in cases with new-onset ESRD, and 11% in those who remained proteinuric during follow-up (P = 0.9, 6 df). Similarly, frequency of the T allele varied little among the same groups (range, 33% to 36%; P = 0.9, 3 df) During follow-up, 52 of 323 individuals with diabetic nephropathy died. Total mortality rates were 4.3/100 person-years in TT homozygotes, 2.4/100 person-years in CT heterozygotes, and 3.0/100 person-years in CC homozygotes (P = 0.55, 2 df). CONCLUSION: Using both a large case-control and a follow-up study, we found no evidence that the C677T MTHFR polymorphism has a significant role in the development of diabetic nephropathy in type 1 diabetes.

Homozygous combination of calpain 10 gene haplotypes is associated with type 2 diabetes mellitus in a Polish population.

OBJECTIVE: The polymorphisms of two genes have recently been associated with complex forms of type 2 diabetes mellitus (T2DM): calpain 10 and peroxisome proliferator-activated receptor-gamma (PPARgamma). Calpain 10 is a member of a large family of intracellular proteases. It was shown in Mexican-Americans and other populations that variants of three single nucleotide polymorphisms (SNPs), -43, -19, and -63, of this ubiquitously expressed protein influence susceptibility to T2DM. However, substantial differences were shown between ethnic groups in at risk alleles and haplotypes as well as in their attributable risk. Thus, it is important to determine the role of calpain 10 in various populations. AIM: To examine the role of calpain 10 SNPs -43, -19, and -63 in genetic susceptibility to T2DM in a Polish population. METHODS: Overall, 377 individuals were examined: 229 T2DM patients and 148 control individuals. The groups were genotyped for calpain 10 SNP-43, SNP-19, and SNP-63. SNP-19 was examined by electrophoresis of the PCR product on agarose gel by size, while the restriction fragment length polymorphism (RFLP) method was used for the two other markers. Differences in allele, genotype, haplotype, and haplotype combination distribution between the groups were examined by chi(2) test. RESULTS: Distributions of alleles, genotypes, and haplotypes at three loci defined by examined SNPs were not significantly different between the groups. However, the homozygote combination of 121 haplotype was more prevalent in the T2DM group than in the controls (17.9% vs 10.1%, P=0.039). No difference was observed in the 112/121 haplotype distribution. This heterozygous haplotype combination was associated with increased risk of T2DM in several populations. CONCLUSION: The results of our study suggest the association of calpain 10 121/121 haplotype combination created by SNPs -43, -19, and -63 with T2DM in a Polish population. However, we were not able to confirm the previously described role of the heterozygous 112/121 haplotype combination in susceptibility to T2DM.