Olga T. Hardy

What causes the insulin resistance underlying obesity

Purpose of reviewThe association between obesity and insulin resistance is an area of much interest and enormous public health impact, with hundreds of articles being published in the last year focused on the possible mechanisms that underlie this association. The purpose to this review is to highlight some of the key recent literature with emphasis on emerging concepts. Recent findingsThe specific link between visceral adipose tissue accumulation and insulin resistance continues to be discerned. Visceral adiposity is correlated with accumulation of excess lipid in liver, and results in cell autonomous impairment in insulin signaling. Visceral adipose tissue is also prone to inflammation and inflammatory cytokine production, which also contribute to impairment in insulin signaling. The expansion of visceral adipose tissue and excess lipid accumulation in liver and muscle may result from limited expandability of subcutaneous adipose tissue, due to the properties of its extracellular matrix and capacity for capillary growth. SummaryRecent studies underscore the need to better understand the mechanisms linking visceral adiposity with liver fat accumulation, the mechanisms by which ectopic fat accumulation cause insulin resistance, and the mechanisms by which the size of adipose tissue depots is determined.

Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity.

BACKGROUND Obesity is a strong risk factor for resistance to insulin-mediated glucose disposal, a precursor of type 2 diabetes and other disorders. However, not all obese individuals are insulin resistant. We sought to identify the molecular pathways that might cause obesity-associated insulin resistance in humans by studying the morbidly obese who were insulin sensitive versus insulin resistant, thereby eliminating obesity as a variable. METHODS Combining gene expression profiling with computational approaches, we determined the global gene expression signatures of omental and subcutaneous adipose tissue samples obtained from similarly obese patients undergoing gastric bypass surgery. RESULTS Gene sets related to chemokine activity and chemokine receptor binding were identified as most highly expressed in the omental tissue from insulin-resistant compared with insulin-sensitive subjects, independent of the body mass index. These upregulated genes included chemokines (C-C motif) ligand 2, 3, 4, and 18 and interleukin-8/(CC-X motif) ligand 8 and were not differentially expressed in the subcutaneous adipose tissues between the 2 groups of subjects. Insulin resistance, but not the body mass index, was associated with increased macrophage infiltration in the omental adipose tissue, as was adipocyte size, in these morbidly obese subjects. CONCLUSION Our findings have demonstrated that inflammation of the omental adipose tissue is strongly associated with insulin resistance in human obesity even in subjects with similar body mass index values.

Long-Term Non-Surgical Therapy of Severe Persistent Congenital Hyperinsulinism with Glucagon

Background: Congenital hyperinsulinism (CHI) is characterized by severe hypoglycemia caused by dysregulated insulin secretion. The long-term outcome is dependent on prevention of hypoglycemic episodes to avoid the high risk of permanent brain damage. Severe cases are usually resistant to diazoxide or nifedipine. In addition, somatostatin analogues are ineffective in a subgroup of patients to achieve stable euglycemia. In these infants the only remaining long-term option has been subtotal pancreatectomy with high risk of diabetes mellitus. Intravenous infusions of glucagon are used as immediate treatment to stabilize euglycemia in affected newborns. The rationale of this treatment comes from the observation of an increased glycogen content of the liver when glycogenolysis is inhibited by insulin. Objective: To review the efficacy and safety of long-term subcutaneous glucagon infusion as a potential therapeutic option for blood glucose stabilization in infants with severe CHI without the need of additional intravenous glucose or immediate surgical intervention. Method: Retrospective review of 9 children with CHI who received continuous subcutaneous infusion of glucagon for weeks or months. Glucagon was added to octreotide to replace octreotide-induced suppression of endogenous glucagon secretion, thereby liberating glucose by stimulation of hepatic glycogenolysis. In 3 cases, a stabilized formulation of glucagon was used to prevent glucagon crystallization that frequently occurs in smaller volumes. Results: Introduction of glucagon allowed the reduction or discontinuation of central glucose infusion in all children studied. In 2 patients, glucagon was introduced due to recurrent hypoglycemia despite subtotal pancreatectomy. Six out of 9 children were discharged home on this treatment, which their parents were able to continue without further symptomatic hypoglycemia, convulsions or unconsciousness. In 3 children, subcutaneous glucagon was continuously administered for 1–4 years leading to stable euglycemia. However, 2 children with diffuse type still required subtotal pancreatectomy. As a possible side effect, 2 children developed erythema necrolyticum, which resolved after discontinuation of the glucagon infusion. This has been described before in glucagonoma. Conclusion: In this retrospective series, combination therapy of low-dose octreotide and subcutaneous glucagon infusion has been effective in preventing hypoglycemic episodes in severe CHI. We propose this may serve as a therapeutic option in place of high rates of glucose infusion through a central venous catheter and as an alternative to subtotal pancreatectomy in diffuse type of CHI.

Increased toll-like receptor (TLR) mRNA expression in monocytes is a feature of metabolic syndrome in adolescents

Metabolic syndrome (MetSyn) is diagnosed frequently in some but not all overweight adolescents. Chronic inflammation, as seen in obesity, is strongly associated with MetSyn.

Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion

Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice, lipogenic genes are upregulated in eWAT, as is Ucp1 in brown fat, while liver triglyceride accumulation is attenuated. Despite expanded eWAT, transgenic animals display improved systemic insulin sensitivity, decreased collagen deposition and inflammation in eWAT, and increased insulin stimulation of Akt phosphorylation. Our data suggest that TNMD acts as a protective factor in visceral adipose tissue to alleviate insulin resistance in obesity.

Hypothyroidism in Down Syndrome: Screening Guidelines and Testing Methodology

Individuals with Down syndrome (DS) are at an increased risk of developing thyroid disease, primarily autoimmune, with a lifetime prevalence ranging from 13% to 63% [Mattheis, 1997]. Fort et al. [1984] also found congenital hypothyroidism to be about 28 times more common among infants with DS than in the general population with an incidence of 1% (0.7% permanent and 0.3% transient congenital hypothyroidism) detected by newborn screening. Beyond the newborn period, the incidence of elevated TSH values in DS increases and has been reported to be as high as 85% of infants under the age of 12 months [Sharav et al., 1988]. This is a treatable cause of mental retardation, thus early detection and treatment are essential in order to maximize cognitive abilities in this already impaired population. Unfortunately, there are few studies systematically examining the frequency of thyroid disease in very young children. Current health supervision guidelines for children with DS suggest reviewing results of the newborn thyroid function screen, then repeating thyroid function tests at the age of 6 months and 12 months, and then annually [Cunniff et al., 2001].

Body mass index, treatment practices, and mortality in patients with acute heart failure

ObjectivesObesity is associated with an increased risk of heart failure (HF). Among patients presenting with acute HF, however, differences in clinical characteristics, treatment regimens, and short-term prognosis of varying weights are largely unknown, particularly from a broader population-based perspective. MethodsA total of 3722 patients admitted with acute HF to 11 greater Worcester (Massachusetts, USA) hospitals during 1995 and 2000 were categorized as being lean (n = 216), normal weight (n = 1465), overweight (n = 1007), or obese (n = 1034) at the time of hospitalization. ResultsObese patients with decompensated HF were significantly younger (mean age = 71 years) compared with patients of normal weight (mean age = 79 years). Obese patients were more likely to have a history of diabetes and have previously undergone a percutaneous coronary intervention than patients of normal body weight. Lean patients (body mass index<18.5 kg/m2) were less likely to be treated with effective cardiac therapies than normal weight patients, whereas obese patients were more likely to be treated with diuretics. Obese patients experienced a significantly lower in-hospital (4.3 vs. 7.2%) and 30-day (7.3 vs. 14.5%) death rate than normal weight patients, whereas lean patients experienced the highest in-hospital (10.2%) and 30-day (19.9%) death rates. ConclusionThe results of this study in residents of a large central New England metropolitan area suggest that obesity is associated with increased survival in patients with acute HF. Further assessment of the ‘obesity paradox’, and careful attention to patients with a low body mass index, in patients with decompensated HF is warranted.

Congenital hyperinsulinism - a review of the disorder and a discussion of the anesthesia management.

Summary Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. In most affected infants, CHI is caused by a specific genetic defect that results in the altered expression of pancreatic beta cells causing unregulated oversecretion of insulin. Infants with CHI may have either focal or diffuse abnormalities of the pancreatic β‐cells. Both forms of CHI manifest as hypoglycemia, usually in the early newborn period. Focal disease can be treated effectively with surgical resection of the affected area, resulting in a total cure or rendering the patient amenable to medical management. Most children with diffuse disease are unresponsive to medical therapy, and require near‐total pancreatectomy. At The Childrens Hospital of Philadelphia, we have developed a multidisciplinary program for diagnosis and treatment of CHI. Anesthesiologists have played an integral role in the perioperative care of these infants, which includes diagnostic procedures, partial or near‐total pancreatectomy, and postoperative pain management. In this review, we describe the clinical features, diagnostic methods and anesthetic concerns in children with CHI.

Effects of a multicomponent wellness intervention on dyslipidemia among overweight adolescents

Abstract Behavioral changes are the first line of treatment for dyslipidemia in adolescents, but outcome data on the effectiveness of this approach are inconsistent. This study aims to assess the effect of a 13-week multicomponent wellness intervention program, which included weekly nutrition classes and structured cardiovascular, flexibility, and strength training on dyslipidemia in nine overweight/obese [body mass index (BMI) ≥85th percentile] and nine lean (BMI <85th percentile) adolescents. Clinical measurements and lipid profile assessment were performed before and after the intervention. At the completion of the study, the overweight/obese adolescents demonstrated a 15% increase in high-density lipoprotein cholesterol (HDL-C) levels (mean, 47±8 vs. 54±5 mg/dL), whereas there was no improvement in BMI or other measurements. The participants in the lean group showed no change in their anthropometric and serum parameters. A multicomponent wellness intervention resulted in a significant increase of cardioprotective HDL-C levels, which have been associated with coronary health in adulthood.

Hyperinsulinism of Infancy: Localization of Focal Forms

Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children (1). Infants with severe forms of the disorder (formerly termed nesidioblastosis) present with hypoglycemia in the newborn period and are at high risk of seizures, permanent brain damage, and retardation. Infants with congenital hyperinsulinism may have either focal or diffuse abnormalities of the pancreatic β cells. In cases with diffuse disease, an underlying defect in the β-cell adenosoine triphosphate (ATP)-dependent potassium channel may be present, caused by recessive loss of function mutations of the two genes encoding the KATP channel, SUR1 or Kir6.2 (1,2). These mutations may also cause focal hyperinsulinism in which there is an area of β-cell adenomatosis due to loss of heterozygosity for the maternal 11p region and expression of a paternally derived KATP channel mutation (3). Most of the cases with severe hyperinsulinism do not respond to medical therapy with diazoxide, octreotide (Fig. 27B.1), or continuous feedings and require near-total pancreatectomy to control hypoglycemia. However, cases of focal hyperinsulinism can be treated effectively with partial pancreatectomy. The surgical approach and therapeutic outcome for the infants depends on preoperatively distinguishing between focal and diffuse forms of hyperinsulinism. This chapter describes the focal lesions of hyperinsulinism, the pancreatectomy procedure, previous methods of determining the site of focal lesions, and the rationale for using positron emission tomography (PET) scans with 18F-fluoro-L-DOPA.