Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A Gene

BACKGROUND: Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS: We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS: HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life

Non-equivalent role of TM2 gating hinges in heteromeric Kir4.1/Kir5.1 potassium channels

Comparison of the crystal structures of the KcsA and MthK potassium channels suggests that the process of opening a K+ channel involves pivoted bending of the inner pore-lining helices at a highly conserved glycine residue. This bending motion is proposed to splay the transmembrane domains outwards to widen the gate at the “helix-bundle crossing”. However, in the inwardly rectifying (Kir) potassium channel family, the role of this “hinge” residue in the second transmembrane domain (TM2) and that of another putative glycine gating hinge at the base of TM2 remain controversial. We investigated the role of these two positions in heteromeric Kir4.1/Kir5.1 channels, which are unique amongst Kir channels in that both subunits lack a conserved glycine at the upper hinge position. Contrary to the effect seen in other channels, increasing the potential flexibility of TM2 by glycine substitutions at the upper hinge position decreases channel opening. Furthermore, the contribution of the Kir4.1 subunit to this process is dominant compared to Kir5.1, demonstrating a non-equivalent contribution of these two subunits to the gating process. A homology model of heteromeric Kir4.1/Kir5.1 shows that these upper “hinge” residues are in close contact with the base of the pore α-helix that supports the selectivity filter. Our results also indicate that the highly conserved glycine at the “lower” gating hinge position is required for tight packing of the TM2 helices at the helix-bundle crossing, rather than acting as a hinge residue

Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient

Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFα or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment

Reversible changes in pancreatic islet structure and function produced by elevated blood glucose

Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized

Voltage-Dependent Gating in a “Voltage Sensor-Less” Ion Channel

An unusual mechanism of ion channel regulation generates voltage-dependent gating in the absence of a canonical voltage-sensing domain

Genetički polimorfizmi u dijabetesu: Utjecaj na terapiju oralnim antidijabeticima

Due to new genetic insights, etiologic classification of diabetes is under constant scrutiny. Hundreds, or even thousands, of genes are linked with type 2 diabetes. Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to be predisposed to type 2 diabetes mellitus across many large studies. Individually, each of these polymorphisms is only moderately predisposed to type 2 diabetes. On the other hand, monogenic forms of diabetes such as MODY and neonatal diabetes are characterized by unique clinical features and the possibility of applying a tailored treatment. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of a number of medications. Mutations in genes important in drug absorption, distribution, metabolism and excretion (ADME) play a critical role in pharmacogenetics of diabetes. There are currently five major classes of oral pharmacological agents available to treat type 2 diabetes: sulfonylureas, meglitinides, metformin (a biguanide), thiazolidinediones, and α-glucosidase inhibitors. Other classes are also mentioned in literature. In this work, different types of genetic mutations (mutations of the gene for glucokinase, HNF 1, HNF1ß and Kir6.2 and SUR1 subunit of KATP channel, PPAR-γ, OCT1 and OCT2, cytochromes, direct drug-receptor (KCNJ11), as well as the factors that influence the development of the disease (TCF7L2) and variants of genes that lead to hepatosteatosis caused by thiazolidinediones) and their influence on the response to therapy with oral antidiabetics will be reviewed.Dijabetes tipa 2 dosegao je proporcije epidemije u SAD (> 18 milijuna) i cijelom svijetu (170 milijuna oboljelih osoba) te ima tendenciju daljnjeg dramatičnog rasta. Stoga se u posljednje vrijeme ulažu napori da se otkriju i razviju novi farmakološki agensi za liječenje ove bolesti. Klasifikacija šećerne bolesti proširena je uspjesima istraživača na području genetike. Da bismo razumjeli farmakogenetiku antidijabetika neophodno je razumjeti genetiku samog dijabetesa. Kao što će biti prikazano u ovom radu veliki broj gena koji su povezani s razvojem dijabetesa takođe utječu i na odgovor na terapiju antidijabeticima. S druge strane, mutacije gena koji utječu na ADME (apsorpcija, distribucija, metabolizam i ekskrecija) lijeka imaju značajan utjecaj na farmakogenetiku oralnih antidijabetika. Utvrđeno je da je dijabetes genetički heterogena bolest. Uobičajeni oblici dijabetesa su gotovo uvijek poligenski i za razvoj same bolesti vrlo su značajne snažne interakcije među različitim genima kao i između gena i okoliša. Zbog toga mutacije ili polimorfizmi koji u manjoj mjeri utječu na funkciju gena mogu postati klinički značajni samo u slučaju kada se kombiniraju s drugim faktorima odnosno genima. Smatra se da u razvoju dijabetesa mogu sudjelovati stotine pa čak i tisuće gena. Do 2006. identificirano je nekoliko uobičajenih alela koji povećavaju rizik za razvoj dijabetesa, od kojih su najznačajniji PPARG (Pro12), KCNJ11 (Lys23) i TCF7L2 (T na rs7903146). Do danas je najveći uspjeh postignut u identifikaciji gena odgovornih za razmjerno rijetke oblike ove bolesti poput ”Maturity-onset diabetes of the young” (MODY) i neonatalnog dijabetesa. Monogenske oblike dijabetesa odlikuju jedinstvene kliničke karakteristike i mogućnost primjene individualnog tretmana. Genetički polimorfizmi enzima koji utječu na metabolizam lijekova, transportera, receptora i drugih ciljeva djelovanja lijekova povezani su s interindividualnim razlikama u efikasnosti i toksičnosti mnogih lijekova. Vrlo je važno da se na temelju farmakogenetičkih istraživanja mogu predvidjeti neki neželjeni efekti lijekova. Trenutačno postoji pet glavnih klasa oralnih antidijabetika: sulfoniluree, meglitinidi, metformin (bigvanid), tiazolidindioni i inhibitori α-glukozidaze. U literaturi se također spominju inhibitori dipeptidil peptidaze IV (DPP-IV), selektivni antagonisti kanabinoidnog receptora 1 (CB-1), glukagonu slični peptid 1 mimetici i amilin mimetici. Razumijevanje mehanizama koji rezultiraju disfunkcijom β stanica na fiziološkom i molekularnom nivou neophodno je za napredak u razumijevanju tretmana dijabetesa. U ovom radu dat je pregled različitih genetičkih mutacija (mutacije gena za glukokinazu, HNF 1, HNF1ß, Kir6.2 i SUR 1 podjedinicu KATP kanala ß stanica, PPAR-γ, OCT1 i OCT2, citohrome, KCNJ11, faktore koji utječu na razvoj bolesti (TCF7L2) i varijante gena koji dovode do hepatosteatoze uzrokovane tiazolidindionima) te njihov utjecaj na odgovor na terapiju oralnim antidijabeticima