The Mental Health Comorbidities of Diabetes Ducat, Lee; Philipson, Louis H; Anderson, Barbara J
JAMA : the journal of the American Medical Association,
08/2014, Letnik:
312, Številka:
7
Journal Article
Recenzirano
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People living with type 1 or type 2 diabetes are at increased risk of mental health comorbidities of diabetes such as depression, anxiety, and eating disorders. If these mental health comorbidities ...of diabetes are not diagnosed and treated in time, the financial cost to society and health care systems is substantial, as are the morbidity and health consequences for patients. Routine screening of diabetes patients for psychosocial problems must be carried out, and people with diabetes should be given medical care from a team that includes physicians, nurse practitioners, dietitians, pharmacists and mental health professionals.
Maturity‐onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ...ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1–6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK‐MODY, HNF1A‐MODY, and HNF4A‐MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK‐MODY), some others are highly responsive to oral agents (i.e., HNF1A‐MODY). The risk of micro‐ and macro‐vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50–90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision‐making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.
In this mini‐review, we summarize the history of maturity‐onset of diabetes of the young (MODY), commonly encountered MODY forms, the clinical characteristics that should lead to MODY suspicion, and practical tips from diagnosis to management. In the era of exponential growth in genetics with its role in precision medicine in various disease states, our mini‐review highlights its utility in the field of diabetes and provides another convincing argument for expanding the accessibility of comprehensive genetic testing for all who deserve it.
Purpose of Review
We provide a review of monogenic diabetes in young children and adolescents with a focus on recognition, management, and pharmacological treatment.
Recent Findings
Monogenic forms ...of diabetes account for approximately 1–2% of diabetes in children and adolescents, and its incidence has increased in recent years due to greater awareness and wider availability of genetic testing. Monogenic diabetes is due to single gene defects that primarily affect beta cell function with more than 30 different genes reported. Children with antibody-negative, C-peptide-positive diabetes should be evaluated and genetically tested for monogenic diabetes. Accurate genetic diagnosis impacts treatment in the most common types of monogenic diabetes, including the use of sulfonylureas in place of insulin or other glucose-lowering agents or discontinuing pharmacologic treatment altogether.
Summary
Diagnosis of monogenic diabetes can significantly improve patient care by enabling prediction of the disease course and guiding appropriate management and treatment.
The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. During periods of feeding, ...pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock and Bmal1 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective -cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the -cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We quantitatively analyzed particle tracking data on insulin granules expressing fluorescent fusion proteins in MIN6 cells to better understand the motions contributing to intracellular transport ...and, more generally, the means for characterizing systems far from equilibrium. Care was taken to ensure that the statistics reflected intrinsic features of the individual granules rather than details of the measurement and overall cell state. We find anomalous diffusion. Interpreting such data conventionally requires assuming that a process is either ergodic with particles working against fluctuating obstacles (fractional Brownian motion) or nonergodic with a broad distribution of dwell times for traps (continuous-time random walk). However, we find that statistical tests based on these two models give conflicting results. We resolve this issue by introducing a subordinated scheme in which particles in cages with random dwell times undergo correlated motions owing to interactions with a fluctuating environment. We relate this picture to the underlying microtubule structure by imaging in the presence of vinblastine. Our results provide a simple physical picture for how diverse pools of insulin granules and, in turn, biphasic secretion could arise.
The pancreatic islet is a highly vascularized endocrine micro-organ. The unique architecture of rodent islets, a so-called core-mantle arrangement seen in two-dimensional images, led researchers to ...seek functional implications for islet hormone secretion. Three models of islet blood flow were previously proposed, all based on the assumption that islet microcirculation occurs in an enclosed structure. Recent electrophysiological and molecular biological studies using isolated islets also presumed unidirectional flow. Using intravital analysis of the islet microcirculation in mice, we found that islet capillaries were continuously integrated to those in the exocrine pancreas, which made the islet circulation rather open, not self-contained. Similarly in human islets, the capillary structure was integrated with pancreatic microvasculature in its entirety. Thus, islet microcirculation has no relation to islet cytoarchitecture, which explains its well-known variability throughout species. Furthermore, tracking fluorescent-labeled red blood cells at the endocrine-exocrine interface revealed bidirectional blood flow, with similar variability in blood flow speed in both the intra- and extra-islet vasculature. To date, the endocrine and exocrine pancreas have been studied separately by different fields of investigators. We propose that the open circulation model physically links both endocrine and exocrine parts of the pancreas as a single organ through the integrated vascular network.
Update on diabetes classification Thomas, Celeste C; Philipson, Louis H
The Medical clinics of North America
99, Številka:
1
Journal Article
Recenzirano
This article highlights the difficulties in creating a definitive classification of diabetes mellitus in the absence of a complete understanding of the pathogenesis of the major forms. This brief ...review shows the evolving nature of the classification of diabetes mellitus. No classification scheme is ideal, and all have some overlap and inconsistencies. The only diabetes in which it is possible to accurately diagnose by DNA sequencing, monogenic diabetes, remains undiagnosed in more than 90% of the individuals who have diabetes caused by one of the known gene mutations. The point of classification, or taxonomy, of disease, should be to give insight into both pathogenesis and treatment. It remains a source of frustration that all schemes of diabetes mellitus continue to fall short of this goal.
Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a ...computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of critical regulatory sites, how different GPCRs interact and pharmacological targets for modulating insulin secretion in type 2 diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approach to the Patient with MODY-Monogenic Diabetes Broome, David T; Pantalone, Kevin M; Kashyap, Sangeeta R ...
The journal of clinical endocrinology and metabolism,
01/2021, Letnik:
106, Številka:
1
Journal Article
Recenzirano
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Abstract
Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed ...despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c HbA1c, glutamic acid decarboxylase antibodies GADA, islet antigen 2 antibodies IA-2A, and zinc transporter 8 ZnT8 antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants).
Learning Objectives
Upon completion of this educational activity, participants should be able to:
Identify risk factors and learn when to suspect MODY-monogenic diabetes
Obtain appropriate diagnostic testing and evaluation prior to treatment
Determine appropriate monitoring and treatment for microvascular and macrovascular comorbidities
Recognize the recommended approach to treatment and monitoring that was performed in a patient with MODY-monogenic diabetes.
Target Audience
This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.
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