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Ekaterine Bakhtadze

Exploring the Grey Zone between Type 1 and Type 2 Diabetes

T1D is most common in children and young adults and is characterized by

autoimmune destruction of insulin producing pancreatic beta cells, presence of certain risk genotypes such as HLA-DQB1, INS VNTR, PTPN22 and need of

insulin for survival. In adults the same situation is often referred to as Latent Autoimmune Diabetes in Adults (LADA), with age at onset after 35 years and non-insulin requiring at least for 6 month after diagnosis. On the other hand, T2D is characterized by impaired insulin secretion and/or insulin resistance, which coexists with excessive hepatic glucose production and abnormal fat metabolism. Environmental factors causing insulin resistance are puberty, pregnancy, weight gain (central obesity “apple type”) and sedentary lifestyle. Usually T2D is diagnosed after 40 years of age and in some cases is diagnosed when patients develop vascular and neuropathic complications. TCF7L2 is by far the strongest T2D-associated gene. Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes inherited in an autosomal dominant fashion (individual has one copy of a mutant gene and one normal gene on a pair of autosomal chromosomes) characterized by nonketotic diabetes, age at onset before 25 years and primarily defect in beta-cell function. Until now, mutations in six genes have been identified as the cause of different forms of MODY, i.e. HNF-4 (MODY 1), glucokinase (GCK) (MODY 2), HNF-1 (MODY 3), IPF1 (MODY 4), HNF-1ß, formerly TCF2 (MODY 5) and NeuroD1 (MODY6). The goal of this thesis was to genetically dissect autoimmune (T1D and LADA) and non-autoimmune (T2D and MODY) diabetes in young (15-34 years old)and middle-aged (40-59 years old) Swedish diabetic patients for proper diagnosis and treatment of the disease in the future. To fulfill our goals we have selected 1642 young (15-34 years old) adult diabetic patients from Diabetes Incidence Study in Sweden (DISS) and 1619 middle-aged (40-59 years old) diabetic patients from Diabetes Registry in Southern Sweden. We determined genetic markers: HLA-DQB1 (study I and II), PTPN22, Ins VNTR, TCF7L2 (study II), PPARG, KCNJ11, IGF2BP2, WFS1, CDKAL1, JAZF1, CDKN2A/2B, HHEX, SLC30A8 and FTO (study III) and MODY genes- HNF-4 , GCK, HNF-1 and HNF-1ß, formerly TCF2 (study IV), measured islet antibodies (ICA, IA-2A and GADA) and C-peptide (marker of beta-cell function instead of insulin).

In Study I we evaluated whether HLA-DQB1 genotypes facilitates the classification of diabetes as compared with islet antibodies among young (15-34 years) adult diabetic patients. Islet antibodies were found among 83% clinically considered to have T1D, 23% with T2D and 45% with unclassifiable diabetes.fpC-peptide concentrations after diagnosis were markedly lower in patients with than in those without islet antibodies. Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one risk HLA-DQB1 genotypes compared with patients without. Antibody negative patients with risk HLA-DQB1 genotypes had significantly lower fasting fpC-peptide concentrations than those without risk genotypes. We concluded that Assessment of islet antibodies is necessary for an etiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with fpC-peptide measurement may be of value in the differentiation between idiopathic T1D versus T2D.

In Study II we evaluated whether genetic markers associated with T1D (HLADQB1,INS VNTR and PTPN22) and T2D (TCF7L2) could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and

middle-aged (40-59 years) diabetic patients. Frequency of risk genotypes HLADQB1, PTPN22 CT/TT, INS VNTR class I/I and INS VNTR class IIIA/IIIA was

increased in young and middle-aged GADA+ compared with GADA- patients.

T2D-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly

more common in young GADA- than in GADA+ patients. No such difference

was seen in middle-aged patients, in whom the frequency of the CT/TT

genotypes of TCF7L2 was similarly increased in GADA- and GADA+ groups.

We concluded that common variants in the TCF7L2 gene help to differentiate

young but not middle aged GADA+ and GADA- diabetic patients, suggesting

that young GADA- patients have T2D and that middle-aged GADA+ patients

(LADA) are different from their young GADA-positive (T1D) counterparts and

share genetic features with T2D.

In Study III we genotyped a panel of 10 novel T2D-associated risk genotypes in young (15-34 years) and middle-aged (40-59 years) GADA+ and GADA- diabetic patients and evaluated how they would modify the clinical phenotype. Young GADA- patients had increased frequency of risk variants in the PPARG, IGF2BP2, WFS1, JAZF1 and CDKN2A/2B genes compared with an elderly nondiabetic control group. Also risk variants in JAZF1 (AA) and CDKN2A/2B (TT) were more common in GADA- than in GADA + young diabetic patients. As expected middle-aged GADA- patients had increased prevalence of risk variants in the PPARG, IGF2BP2, WFS1, CDKAL1, JAZF1, SLC30A8, CDKN2A/2B, KCNJ11 and FTO genes compared with non-diabetic controls with no significant difference compared with GADA+ patients. Middle-aged GADA diabetic patients with more risk alleles (≥12) had decreased C-peptide concentrations than patients with less risk alleles (≤9). Also, GADA+ patients with more risk alleles had an earlier age at onset than GADA+ patients with less risk alleles. Distribution of T2D-associated risk alleles was quite similar inmiddle-aged patients regardless of presence of GADA. T2D- associated risk genotypes modify the disease phenotype (age at onset and C-peptide) in middleaged but not in young diabetic patients.

In Study IV we evaluated whether common variants in MODY genes can

discriminate between autoimmune and non-autoimmune diabetes in young adult

diabetic patients and screened antibody negative diabetic patients with 3

members with diabetes in the family for HNF-4 , GCK and HNF-1 mutations.

No significant difference in frequency of common variants in MODY genes was

seen between Ab+ and Ab- individuals. In Ab+ diabetic patients carriers of the T2D-associated T allele of the HNF-1 gene had higher age at onset of diabetes, but severe symptoms of diabetes (weight reduction and/or polyuria) than G allele carriers. Finally, in Ab- diabetic patients carriers of the T2D-associated G allele of HNF-1ß gene had less frequent weight reduction and/or polyuria and ketonuria at diagnosis than A allele careers. One patient had frameshift mutation in exon 4 designated “Pro291fsinsC” in the HNF-1 gene. Common variants in MODY genes do not discriminate between young patients with autoimmune and non-autoimmune diabetes but they do influence onset and presentation of the disease.

Our studies show that genetic markers clearly improve the classification of

diabetes and together with islet antibodies they might be of help for diagnosis and treatment of different diabetic subgroups.

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