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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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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.
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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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Favourable metabolic effects of a eucaloric lower-carbohydrate diet in women with PCOS.
Gower, BA, Chandler-Laney, PC, Ovalle, F, Goree, LL, Azziz, R, Desmond, RA, Granger, WM, Goss, AM, Bates, GW
Clinical endocrinology. 2013;(4):550-7
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OBJECTIVE Diet-induced reduction in circulating insulin may be an attractive nonpharmacological treatment for women with polycystic ovary syndrome (PCOS) among whom elevated insulin may exacerbate symptoms by stimulating testosterone synthesis. This study was designed to determine whether a modest reduction in dietary carbohydrate (CHO) content affects β-cell responsiveness, serum testosterone concentration and insulin sensitivity in women with PCOS. DESIGN In a crossover design, two diets ('Standard,' STD, 55:18:27% energy from carbohydrate/protein/fat; lower-carbohydrate, 41:19:40) were provided for 8 weeks in random order with a 4-week washout between. PATIENTS Thirty women with PCOS. MEASUREMENTS β-cell responsiveness assessed as the C-peptide response to glucose during a liquid meal test; insulin sensitivity from insulin and glucose values throughout the test; insulin resistance (HOMA-IR); and total testosterone by immunoassay. RESULTS Paired t-test indicated that the lower-CHO diet induced significant decreases in basal β-cell response (PhiB), fasting insulin, fasting glucose, HOMA-IR, total testosterone and all cholesterol measures, and significant increases in insulin sensitivity and dynamic ('first-phase') β-cell response. The STD diet induced a decrease in HDL-C and an increase in the total cholesterol-to-HDL-C ratio. Across all data combined, the change in testosterone was positively associated with the changes in fasting insulin, PhiB and insulin AUC (P < 0·05). CONCLUSIONS In women with PCOS, modest reduction in dietary CHO in the context of a weight-maintaining diet has numerous beneficial effects on the metabolic profile that may lead to a decrease in circulating testosterone.
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Visceral fat resection in humans: effect on insulin sensitivity, beta-cell function, adipokines, and inflammatory markers.
Lima, MM, Pareja, JC, Alegre, SM, Geloneze, SR, Kahn, SE, Astiarraga, BD, Chaim, ÉA, Baracat, J, Geloneze, B
Obesity (Silver Spring, Md.). 2013;(3):E182-9
Abstract
OBJECTIVE The visceral fat is linked to insulin resistance, the metabolic syndrome, type 2 diabetes and an increased cardiovascular risk, but it is not clear whether it has a causative role. DESIGN AND METHODS Surgical resection of this fat depot is a research model to address this issue. Twenty premenopausal women with metabolic syndrome and grade III obesity were randomized to undergo Roux-en-Y gastric bypass (RYGBP) either alone or combined with omentectomy. Insulin sensitivity (IS; euglycemic-hyperinsulinemic clamp), acute insulin response to glucose (AIR; intravenous glucose tolerance test), disposition index (DI = AIR × IS measured by clamp), lipid profile, adipokine profile (leptin, adiponectin, resistin, visfatin, interleukin-6, TNF-α, MCP-1), ultra-sensitive C-reactive protein (CRP), body composition, and abdominal fat echography were assessed prior to surgery and 1, 6, and 12 months post-surgery. RESULTS Omentectomy was associated with greater weight loss at all time points. IS improved similarly in both groups. Omentectomy was associated to lower CRP after 12 months, but it did not influence adipokines and other metabolic parameters. Among non-diabetic subjects, omentectomy was associated with a preservation of baseline AIR after 12 months (as opposed to deterioration in the control group) and a greater DI after 6 and 12 months. CONCLUSION Although omentectomy did not enhance the effect of RYGBP on insulin sensitivity and adipokines, it was associated with a preservation of insulin secretion, a greater weight loss, and lower CRP.
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Pathophysiology of diabetes mellitus in Cushing's syndrome.
Pivonello, R, De Leo, M, Vitale, P, Cozzolino, A, Simeoli, C, De Martino, MC, Lombardi, G, Colao, A
Neuroendocrinology. 2010;:77-81
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Abstract
Cushing's syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing's syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing's syndrome.
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Physiological regulation of the pancreatic {beta}-cell: functional insights for understanding and therapy of diabetes.
McClenaghan, NH
Experimental physiology. 2007;(3):481-96
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Knowledge about the sites and actions of the numerous physiological and pharmacological factors affecting insulin secretion and pancreatic beta-cell function has been derived from the use of bioengineered insulin-producing cell lines. Application of an innovative electrofusion approach has generated novel glucose-responsive insulin-secreting cells for pharmaceutical and experimental research, including popular BRIN-BD11 beta-cells. This review gives an overview of the establishment and core characteristics of clonal electrofusion-derived BRIN-BD11 beta-cells. As discussed, BRIN-BD11 cells have facilitated studies aimed at dissecting important pathways by which nutrients and other bioactive molecules regulate the complex mechanisms regulating insulin secretion, and highlight the future potential of novel and diverse bioengineering approaches to provide a cell-based insulin-replacement therapy for diabetes. Clonal BRIN-BD11 beta-cells have been instrumental in: (a) characterization of K(ATP) channel-dependent and -independent actions of nutrients and established and emerging insulinotropic antidiabetic drugs, and the understanding of drug-induced beta-cell desensitization; (b) tracing novel metabolic and beta-cell secretory pathways, including use of state-of-the-art NMR approaches to provide new insights into the relationships between glucose and amino acid handling and insulin secretion; and (c) determination of the chronic detrimental actions of nutrients and the diabetic environment on pancreatic beta-cells, including the recent discovery that homocysteine, a risk factor for metabolic syndrome, may play a role in the progressive demise of insulin secretion and pancreatic beta-cell function in diabetes. Collectively, the studies discussed in this review highlight the importance of innovative experimental beta-cell physiology in the discovery and characterization of new and improved drugs and therapeutic strategies to help tackle the emerging diabetes epidemic.