A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations

Szopa, Magdalena; Klupa, Tomasz; Kapusta, Maria; Matejko, Bartłomiej; Ucieklak, Damian; Głodzik, Wojciech; Zapała, Barbara; Sani, C; Hohendorff, Jerzy; Małecki, Maciej T.; Skupień, Jan

doi:10.1007/s12020-019-01863-7

Cited by 13 publications

(16 citation statements)

References 23 publications

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“…However, the relevance of these variants as the sole cause of the diabetes is quite unlikely. Specifically, such monogenic forms of diabetes would most likely be associated with levels of C-peptide much higher than the levels observed in these longevity studies [24]. For example, in a study of 77 individuals with fairly long-duration HNF1α diabetes, the lowest C-peptide level was 0.36 nmol/l, which far exceeded the highest level observed in the Joslin Medalist cohort.…”

Section: Residual Beta Cell Function In Longstanding Diabetesmentioning

confidence: 80%

Discoveries from the study of longstanding type 1 diabetes

et al. 2021

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Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. In this review, we present an overview of the methodological sources of selection bias inherent in survivorship research (selection of those with early-onset diabetes, incidence-prevalence bias and bias from losses to follow-up in cohort studies) and the breadth and depth of literature focusing on this special study population. We focus on the learnings from the study of longstanding type 1 diabetes on discoveries about the natural history of insulin production loss and microvascular complications, and mechanisms associated with them that may in future offer therapeutic targets. We detail descriptive findings about the prevalence of preserved insulin production and resistance to complications, and the putative mechanisms associated with such resistance. To date, findings imply that the following mechanisms exist: strategies to maintain or recover beta cells and their function; activation of specific glycolytic enzymes such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin-angiotensin-aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint proteins. Among the many clinical and public health insights, research into this special study population has identified putative mechanisms that may in future serve as therapeutic targets, knowledge that likely could not have been gained without studying long-term survivors.

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Section: Residual Beta Cell Function In Longstanding Diabetesmentioning

confidence: 80%

Discoveries from the study of longstanding type 1 diabetes

et al. 2021

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“…Authors devised a three-step decision tree algorithm using C-peptide, BMI, 1,5-anhydroglucitol (1,5-AG), and hsCRP to identify patients with HNF1A mutations. Nevertheless, the model was not accurate enough to discriminate HNF1A patients without gene sequencing [68].…”

Section: High-sensitivity C-reactive Protein (Hscrp) and Hnf1amentioning

confidence: 91%

“…Many stepwise algorithms of etiologic diagnoses of hyperglycemia have been proposed [68][69][70]. Recently, Urakami et al suggested an algorithm used to identify candidates with diabetes who should undergo genetic testing considering age at onset of diabetes, pancreatic autoimmunity and residual function, obesity and insulin resistance and some nongenetic biomarkers [71].…”

Section: Phenotype Referencesmentioning

confidence: 99%

Update on clinical screening of maturity-onset diabetes of the young (MODY)

Peixoto-Barbosa

Reis

Giuffrida

2020

Diabetol Metab Syndr

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Background: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes, being characterized by beta-cell disfunction, early onset, and autosomal dominant inheritance. Despite the rapid evolution of molecular diagnosis methods, many MODY cases are misdiagnosed as type 1 or type 2 diabetes. High costs of genetic testing and limited knowledge of MODY as a relevant clinical entity are some of the obstacles that hinder correct MODY diagnosis and treatment. We present a broad review of clinical syndromes related to most common MODY subtypes, emphasizing the role of biomarkers that can help improving the accuracy of clinical selection of candidates for molecular diagnosis. Main body: To date, MODY-related mutations have been reported in at least 14 different genes. Mutations in glucokinase (GCK), hepatocyte nuclear factor-1 homeobox A (HNF1A), and hepatocyte nuclear factor-4 homeobox A (HNF4A) are the most common causes of MODY. Accurate etiological diagnosis can be challenging. Many biomarkers such as apolipoprotein-M (ApoM), aminoaciduria, complement components, and glycosuria have been tested, but have not translated into helpful diagnostic tools. High-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY and have been tested in some studies to discriminate HNF1A-MODY from other types of diabetes, although more data are needed. Overall, presence of pancreatic residual function and absence of islet autoimmunity seem the most promising clinical instruments to select patients for further investigation. Conclusions: The selection of diabetic patients for genetic testing is an ongoing challenge. Metabolic profiling, diabetes onset age, pancreatic antibodies, and C-peptide seem to be useful tools to better select patients for genetic testing. Further studies are needed to define cutoff values in different populations.

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“…Importantly, HNF1A-MODY patients often develop micro- and macrovascular complications, with retinopathy being one of the most prevalent [ 56 , 57 ]. The incidence of vascular complications is similar to patients with T1DM and T2DM [ 58 ]. Moreover, Steele et al showed that 66% of deaths in HNF1A-MODY carriers may be caused by cardiovascular disease or cerebral vascular events, which is a severe threat to this group of patients.…”

Section: Molecular Pathophysiology Of the Most Common Mody Subtypesmentioning

confidence: 99%

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

Skoczek

Dulak

Kachamakova‐Trojanowska

2021

IJMS

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Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.

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A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations

Cited by 13 publications

References 23 publications

Discoveries from the study of longstanding type 1 diabetes

Discoveries from the study of longstanding type 1 diabetes

Update on clinical screening of maturity-onset diabetes of the young (MODY)

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

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