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SYNDROMES OF KETOSIS-PRONE DIABETES.
Balasubramanyam, A
Transactions of the American Clinical and Climatological Association. 2019;:145-155
Abstract
Ketosis-prone diabetes (KPD) is a heterogeneous condition characterized by patients who present with diabetic ketoacidosis but lack the phenotype of autoimmune type 1 diabetes. Here I review progress in our understanding of KPD and its place in the expanding universe of "atypical diabetes." I focus on investigations of our collaborative research group at Baylor College of Medicine and the University of Washington using a longitudinally followed, heterogeneous, multiethnic cohort of KPD patients. We have identified clinically and pathophysiologically distinct KPD subgroups, separable by the presence or absence of islet autoimmunity and the presence or absence of beta cell functional reserve. The resulting "Aß" classification of KPD accurately predicts long-term glycemic control and insulin dependence. I describe key characteristics of the KPD subgroups, their natural histories, and our investigations into their immunologic, genetic, and metabolic etiologies. These studies serve as a paradigm for the investigation of atypical forms of diabetes.
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Cardiorespiratory fitness is positively associated with increased pancreatic beta cell function independent of fatness in individuals with the metabolic syndrome: Fitness versus fatness.
Ramos, JS, Dalleck, LC, Borrani, F, Fassett, RG, Coombes, JS
Journal of science and medicine in sport. 2017;(1):45-49
Abstract
OBJECTIVES The vulnerability of individuals with the metabolic syndrome (MetS) to cardiovascular events (CVEs) is attenuated by increased cardiorespiratory fitness (CRF), despite the presence of obesity as a usual component of MetS. To better understand the importance of CRF and body fat in treating this condition, we investigated the relationship between fitness and fatness with pancreatic beta cell function (BCF) indices that are known independent predictors of CVEs. DESIGN Cross sectional study. METHODS This study included 84 individuals with MetS. BCF indices were derived from a fasted steady state (basal disposition index [DI], proinsulin, proinsulin:insulin, and proinsulin:C-peptide) and dynamic conditions via an oral glucose tolerance test (1st and 2nd phase DI). CRF and body fat percentage (BF%) were assessed via indirect calorimetry (during a maximal exercise test) and dual energy X-ray absorptiometry, respectively. RESULTS CRF was positively associated with basal DI (r=0.40, p<0.001), 1st phase DI (r=0.49, p<0.005), and 2nd phase DI (r=0.38, p=0.02). Hierarchical multiple regression analysis showed CRF was associated with basal DI (β=0.18, p=0.04), 1st phase DI (β=0.36, p=0.04), and 2nd phase DI (β=0.33, p=0.03), independent of BF% and other confounding factors including age, sex, diabetic status, anthropometric measures, lipid profile, and insulin sensitivity. No significant associations were found between CRF and proinsulin measures. BF% was not significantly correlated with BCF indices. CONCLUSIONS Increased CRF was independently associated with enhanced BCF. This study provides evidence that equal, if not more attention should be dedicated to CRF improvement relative to fat-loss for favorable pancreatic BCF and thus possible reduction in CV risk in individuals with MetS.
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The islet circadian clock: entrainment mechanisms, function and role in glucose homeostasis.
Rakshit, K, Qian, J, Colwell, CS, Matveyenko, AV
Diabetes, obesity & metabolism. 2015;(0 1):115-22
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Abstract
Circadian regulation of glucose homeostasis and insulin secretion has long been appreciated as an important feature of metabolic control in humans. Circadian disruption is becoming increasingly prevalent in today's society and is likely responsible in part for the considerable rise in type 2 diabetes (T2DM) and metabolic syndrome worldwide. Thus, understanding molecular mechanisms driving the inter-relationship between circadian disruption and T2DM is important in context of disease prevention and therapeutics. In this regard, the goal of this article is to highlight the role of the circadian system, and islet circadian clocks in particular, as potential regulators of β-cell function and survival. To date, studies have shown that islet clocks respond to changes in feeding patterns, and regulate a multitude of critical cellular processes in insulin secreting β-cells (e.g. insulin exocytosis, mitochondrial function and response to oxidative stress). Subsequently, either genetic or environmental disruption of normal islet clock performance compromises β-cell function and leads to loss of glycaemic control. Future work is warranted to further unravel the role of circadian clocks in human islet function in health and contributions to pathogenesis of T2DM.
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Fatty pancreas, insulin resistance, and β-cell function: a population study using fat-water magnetic resonance imaging.
Wong, VW, Wong, GL, Yeung, DK, Abrigo, JM, Kong, AP, Chan, RS, Chim, AM, Shen, J, Ho, CS, Woo, J, et al
The American journal of gastroenterology. 2014;(4):589-97
Abstract
OBJECTIVES Nonalcoholic fatty liver disease is the most common chronic liver disease. Fatty pancreas has also been described but is difficult to assess. It is now possible to measure pancreatic and liver fat accurately with magnetic resonance imaging (MRI). We aimed to define the normal range of pancreatic fat and identify factors associated with fatty pancreas. In addition, the effect of fatty liver and fatty pancreas on insulin resistance (IR) and pancreatic β-cell function was studied. METHODS Fat-water MRI and proton-magnetic resonance spectroscopy were performed on 685 healthy volunteers from the general population to measure pancreatic and liver fat, respectively. On the basis of fasting plasma glucose and insulin levels, the IR and β-cell function were assessed using the homeostasis model assessment (HOMA). RESULTS Among subjects without significant alcohol consumption or any component of metabolic syndrome, 90% had pancreatic fat between 1.8 and 10.4%. Using the upper limit of normal of 10.4%, 110 (16.1%; 95% confidence interval 13.3-18.8%) subjects had fatty pancreas. On multivariable analysis, high serum ferritin, central obesity, and hypertriglyceridemia were independent factors associated with fatty pancreas. Subjects with both fatty pancreas and fatty liver had higher HOMA-IR than did those with either condition alone. Fatty pancreas was not associated with HOMA-β after adjusting for liver fat and body mass index. CONCLUSIONS In all, 16.1% of this community cohort of adult Hong Kong Chinese volunteers had a fatty pancreas by our definition. Central obesity, hypertriglyceridemia, and hyperferritinemia are associated with fatty pancreas. Individuals with fatty pancreas have increased IR.
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Novel determinants preventing achievement of major cardiovascular targets in type 2 diabetes.
Camara, S, Bouenizabila, E, Hermans, MP, Ahn, SA, Rousseau, MF
Diabetes & metabolic syndrome. 2014;(3):145-51
Abstract
BACKGROUND T2DM management requires tight control of 3 critical quality indicators to prevent vascular complications: LDL-C, SBP, and HbA1c. This study evaluated the rate of T2DM patients attaining these critical quality indicators, and the pathophysiological or cardiometabolic traits predicting goal achievement. PATIENTS AND METHODS Cross-sectional analysis evaluating combined goal achievement (LDL-C<100 mg/dL; SBP<130 mmHg and HbA1c<7.0%) in 1005 T2DM outpatients (654 men) followed in a university hospital multidisciplinary department. Triple-goal achievers were compared to non-achievers regarding sociodemographics; anthropometrics; homeostatic model assessment (HOMA; β-cell function (B); insulin sensitivity (S); hyperbolic product (B×S)); CV and glucose-lowering drugs; micro-/macro-vascular outcomes; and 10-year UKPDS risk. RESULTS Eighty-eight patients (9%; ((3 targets) group) reached all goals, whereas 917 patients (91%; ((0-2 target(s)) group) missed 1, 2 or all 3 goals. Compared to (0-2 target(s)), (3 targets) had shorter diabetes duration; less familial diabetes history; lower waist/visceral fat; higher β-cell function and hyperbolic product (B×S); lower (B×S) loss rate and less metabolic syndrome (all p<0.05). They had lower apoB and triglycerides; and a 28% prevalence of atherogenic dyslipidemia (vs. 40% in (0-2 target(s)); p 0.0398). Microangiopathy (36% vs. 53%) and 10-year CAD risk (13% vs. 18%) were also significantly lower in (3 targets). CONCLUSIONS The subset of T2DM patients achieving all critical quality indicators are characterized by a less severe cardiometabolic phenotype, while exhibiting a less pronounced alteration of their residual β-cell function. These differences are related to fewer microvascular outcomes and lower 10-year CV risk.