Maturity-onset diabetes of the young (MODY) - in search of ideal diagnostic criteria and precise treatment

Zečević, Ksenija; Volčanšek, Špela; Katsiki, Niki; Rizzo, Manfredi; Milardović, Tanja Miličević; Stoian, Anca Pantea; Banach, Maciej; Muzurović, Emir

doi:10.1016/j.pcad.2024.03.004

Cited by 2 publications

(2 citation statements)

References 77 publications

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“…Diabetes mellitus (DM) represents a series of chronic metabolic conditions, biochemically characterized by hyperglycemia resulting from insulin deficiency due to pancreatic β-cell damage (type 1 DM) or peripheral tissue insulin resistance (type 2 DM) (1). Additionally, several other specific types of DM have been classified under a broad category termed maturity-onset diabetes of the young (MODY) (2). Type 2 diabetes mellitus (T2DM), also called non-insulin-dependent DM, is associated with insulin resistance and progressive nonautoimmune β-cell dysfunction (3).…”

Section: Introductionmentioning

confidence: 99%

Preventing Childhood Obesity in Diabetes: A Critical Imperative

Koohmanaee,

Pourkazem,

Hassanzadeh Rad

et al. 2024

J Compr Ped

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: Diabetes mellitus (DM) encompasses a range of chronic metabolic conditions characterized by hyperglycemia, stemming from either insulin deficiency due to pancreatic β-cell damage (T1DM) or peripheral tissue insulin resistance (T2DM). Given the importance of DM and obesity, this narrative review aimed to address the optimal screening and control of childhood obesity as the main strategies for dealing with the comorbidities of T2DM. This review underscores the critical importance of optimal screening and management of childhood obesity as primary strategies for addressing comorbidities associated with T2DM. In many cases, T2DM may remain asymptomatic for several years, leaving patients unaware of their condition or experiencing few symptoms despite having poorly controlled prediabetes or DM. Hence, it is imperative to recognize that screening for prediabetes and childhood obesity presents a crucial opportunity for intervention to avert the future development of DM and its lifelong health repercussions. Moreover, lifestyle modifications stand out as the most effective approach for preventing or delaying the onset of T2DM comorbidities and complications. It is noteworthy that reductions in mortality among people with DM, associated with current antidiabetic medications, will increase the lifetime accumulation of T2DM complications and morbidities worldwide.

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Section: Introductionmentioning

confidence: 99%

Preventing Childhood Obesity in Diabetes: A Critical Imperative

Koohmanaee,

Pourkazem,

Hassanzadeh Rad

et al. 2024

J Compr Ped

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“…For example, glucokinase-maturity-onset diabetes of the young (GK-MODY) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) are caused by inactivating and activating GCK mutations, respectively [ 4 , 5 ]. Individuals with GK-MODY due to inactivating mutations have impaired glucose sensing with a higher setpoint which triggers increased insulin secretion which may lead to mild and asymptomatic fasting hyperglycemia (5.5–8 mmol/L) [ 6 ]. Until the recent introduction of a GK activator known to restore the glucose-sensing and insulin-secreting setpoints [ 7 ], conventional oral antidiabetic drugs (OADs) are not effective among these patients [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

Wang,

Shi,

Luk

et al. 2024

Cardiovasc Diabetol

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Background Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction. Methods Using publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR). Results Genetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57–46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78–4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54–0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results. Conclusions Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

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Maturity-onset diabetes of the young (MODY) - in search of ideal diagnostic criteria and precise treatment

Cited by 2 publications

References 77 publications

Preventing Childhood Obesity in Diabetes: A Critical Imperative

Preventing Childhood Obesity in Diabetes: A Critical Imperative

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

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