1.
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.
2.
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.
3.
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.
4.
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.