Devin Steenkamp

The syndrome of hypoparathyroidism, deafness, and renal anomalies.

OBJECTIVE We review the syndrome of hypoparathyroidism, deafness, and renal anomalies (HDR syndrome). METHODS The current understanding and relevant literature pertaining to the background, genetic considerations, clinical features, prognosis, and treatment of HDR syndrome are reviewed. RESULTS The combination of hypoparathyroidism, deafness, and renal anomalies constitutes an unusual syndrome associated most commonly with haploinsufficiency in GATA3, which encodes a transcription factor that binds to the (A/T) GATA (A/G) consensus DNA sequence. Sensorineural hearing loss is the most consistently expressed clinical feature, being present in almost all affected individuals, and the combination of hypoparathyroidism and hearing impairment occurs in well over 90% of those affected, with various renal anomalies being the most heterogeneous feature of the classic triad. We characterize, in tabular form, the individual cases described in the literature and propose a classification scheme based on the presence or absence of renal anomalies. We also include the specific genetic abnormality and renal anomaly associated with each individual case. CONCLUSION HDR syndrome is a heterogeneous syndrome most commonly associated with GATA3 haploinsufficiency.

Adult Hyperglycemic Crisis: A Review and Perspective

Hyperglycemic crisis, which includes Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State, is a common diagnosis in high acuity hospital units and admission rates continue to increase despite preventive strategies. While diabetic ketoacidosis remains a common cause of death in children and adolescents with type 1 diabetes, in adults reported mortality is variable and depends on the severity of metabolic derangement and the presence of other acute and chronic conditions. Hyperosmolar hyperglycemic state, and the overlap syndrome of hyperosmolar ketoacidosis, have a higher overall mortality though outcomes are improving. We discuss the diagnosis, epidemiology, and management strategies with particular reference to commonly encountered pitfalls in care and provide an updated perspective on the shifts in the epidemiology and novel management strategies for these important disorders.

Type B insulin resistance syndrome.

Purpose of reviewTo review the epidemiology, pathophysiology, clinical features, and management of type B insulin resistance syndrome. Recent findingsType B insulin resistance syndrome is a rare disorder caused by autoantibodies to the insulin receptor. This disorder is most frequently reported in middle-aged black women and is invariably associated with other autoimmune diseases. Typically, refractory transient hyperglycemia and extreme insulin resistance are the cardinal features, but hypoglycemia may also occur. Traditionally, the high reported mortality rate was typically attributed to the hypoglycemia. There is no well standardized treatment regimen. However, recent therapeutic advances with combination immunomodulatory therapy have led to significant reported improvements in hypoglycemia-associated mortality and durability of remission. SummaryWe review the literature on the pathophysiology and clinical features of type B insulin resistance syndrome and highlight the complexities and recent advances in the management of this disorder.

Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis

Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular flux (XF96) analyzers, but the technology remains imperfect for analysis of human lymphocytes. Limitations in XF technology include the lack of practical protocols for analysis of archived human cells, and inadequate data analysis tools that require manual quality checks. Current analysis tools for XF outcomes are also unable to automatically assess data quality and delete untenable data from the relatively high number of biological replicates needed to power complex human cell studies. The objectives of work presented herein are to test the impact of common cellular manipulations on XF outcomes, and to develop and validate a new automated tool that objectively analyzes a virtually unlimited number of samples to quantitate mitochondrial function in immune cells. We present significant improvements on previous XF analyses of primary human cells that will be absolutely essential to test the prediction that changes in immune cell mitochondrial function and fuel sources support immune dysfunction in chronic inflammatory diseases like type 2 diabetes.

An amylin analog used as a challenge test for Alzheimer's disease

Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimers disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans.

Approach to the patient with atypical diabetes.

The overarching term “diabetes mellitus” represents a heterogeneous group of metabolic conditions characterized by hyperglycemia. All of these conditions are underpinned by a combination of various insulin secretory defects and impaired insulin action. According to the American Diabetes

Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca2+ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences in T1D, we quantified a panel of metabolic responses in fibroblasts and peripheral blood cells (PBMCs) from age-matched T1D and non-T1D subjects, as models for non-immune and immune cells, respectively. Fibroblasts from T1D subjects accumulated more lipid, had higher LC-CoA levels and converted more FA to CO2, with less mitochondrial proton leak in response to oleate alone or with TNFα, using the latter as a model of inflammation. T1D-PBMCs contained and also accumulated more lipid following FA exposure. In addition, they formed more peroxidized lipid than controls following FA exposure. We conclude that both immune and non-immune cells in T1D subjects differ from controls in terms of responses to FA and TNFα. Our results suggest a differential sensitivity to inflammatory insults and FA that may precede and contribute to T1D by priming both immune cells and their targets for autoimmune reactions.

Active cocaine use does not increase the likelihood of hyperglycemic crisis

Objective Hyperglycemic crisis encompasses a group of diabetes emergencies characterized by insulin deficiency with high morbidity and mortality. Cocaine use is increasingly prevalent in the United States and may be associated with increased risk of diabetic ketoacidosis. The objective was to determine if active cocaine use at hospital admission could be considered a risk factor for development of hyperglycemic crisis. Methods A retrospective case-control analysis was performed on 950 inpatients with hyperglycemia at an urban academic hospital. Patients admitted with non-emergent hyperglycemia were compared to patients who met criteria for diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and hyperosmolar ketoacidosis (HK), based on the absence or presence of cocaine metabolites on urine toxicology screen. Outcomes included frequency of cocaine use in patients with DKA, HHS, HK, and non-emergent hyperglycemia; phenotypic characteristics of cocaine users vs. non-users with hyperglycemia; phenotypic characteristics of patients with hyperglycemic crisis vs. non-emergent hyperglycemia. Results 950 patients were admitted with hyperglycemia, 133 of which met criteria for hyperglycemic crisis. There was no significant difference in the frequency of cocaine use in individuals with non-emergent hyperglycemia compared to individuals with hyperglycemic crisis (16.9% vs. 17.2%, p = 0.90). 16.9% of patients with DKA, 16.4% of patients with HHS, and 6.4% of patients with HK were cocaine users. Conclusions We found no association between active cocaine use at the time of hospital admission and development of hyperglycemic crisis, when compared to non-emergent hyperglycemia. The role of routine screening for cocaine use in patients with hyperglycemic crisis is unclear.

Atypical diabetes: clarifying the muddy waters

This article was written for the practising primary care clinician, who may occasionally take care of a patient with diabetes who doesn’t seem to fit into our typical diabetes classification paradigm. It is not a comprehensive review of the topic for the expert practising endocrinologist. LADA is

Preserved Proinsulin Production in Homozygous Protein Tyrosine Phosphatase Nonreceptor Type 22 C1858T Variant Type 1 Diabetes: A Possible Explanation for Absence of Overt Ketoacidosis Despite Omission of Exogenous Insulin

OBJECTIVE To report a postulated mechanism for resistance to overt ketoacidosis due to prolonged insulin omission in a severely hyperglycemic woman with a 14-year history of autoimmune type 1 diabetes (T1D). METHODS History, physical examination, laboratory testing, and genotyping were performed. We also review the medical literature pertinent to this patients phenotype and genotype. RESULTS Proinsulin levels remained within the normal range (suppressed with hypoglycemia) despite simultaneous almost unmeasurable C-peptide levels during hyperglycemia. We confirmed a homozygous (TT) variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22) 1858T, a T1D susceptibility gene associated with higher proinsulin levels. CONCLUSION The extraordinarily preserved proinsulin biological activity may explain the unusual resistance to overt ketoacidosis despite omission of exogenous insulin administration for extended periods of time. The role of the associated PTPN22 1858TT variant remains speculative.