Michelle Carey

Reduced Adipose Tissue Macrophage Content Is Associated With Improved Insulin Sensitivity in Thiazolidinedione-Treated Diabetic Humans

Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans.

The clinical impact of inpatient hypoglycemia

Hypoglycemia is common in hospitalized patients and is associated with poor outcomes, including increased mortality. Older individuals and those with comorbidities are more likely to suffer the adverse consequences of inpatient hypoglycemia. Observational studies have shown that spontaneous inpatient hypoglycemia is a greater risk factor for death than iatrogenic hypoglycemia, suggesting that hypoglycemia acts as a marker for more severe illness, and may not directly cause death. Initial randomized controlled trials of intensive insulin therapy in intensive care units demonstrated improvements in mortality with tight glycemic control, despite high rates of hypoglycemia. However, follow-up studies have not confirmed these initial findings, and the largest NICE-SUGAR study showed an increase in mortality in the tight control group. Despite these recent findings, a causal link between hypoglycemia and mortality has not been clearly established. Nonetheless, there is potential for harm from inpatient hypoglycemia, so evidence-based strategies to treat hyperglycemia, while preventing hypoglycemia should be instituted, in accordance with current practice guidelines.

Evidence for Central Regulation of Glucose Metabolism

Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (KATP) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.

Impact of Hypoglycemia in Hospitalized Patients

Hypoglycemia is a common problem in hospitalized patients, particularly the elderly, frail, and severely ill. Hypoglycemia has been implicated in the development of adverse clinical outcomes, including increased mortality. Fear of iatrogenic hypoglycemia remains an obstacle to adequate inpatient glycemic control. However, evidence from large clinical trials is mixed: several intensive care unit studies have shown either reduced or no change in mortality with intensive glycemic control, despite high rates of iatrogenic hypoglycemia, and only 1 large study showed higher mortality. In the general ward setting, the association of hypoglycemia with worse outcomes and mortality has been frequently reported, but after multivariate adjustment for comorbidities this association disappears. Spontaneous hypoglycemia, rather than iatrogenic hypoglycemia, is strongly associated with mortality suggesting that hypoglycemia behaves as a biomarker rather than a causative factor of adverse outcomes. Inpatient glycemic management should be patient-centered, follow the current guidelines, and aimed at preventing hypoglycemia.

Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients.

Objective The American Diabetes Association has called for further research on how patients’ demographics should determine drug choices for individuals with type 2 diabetes mellitus (T2DM). Here, using in-depth physiology studies, we investigate whether obese patients with T2DM are likely to benefit from thiazolidinediones, medications with a known adverse effect of weight gain. Materials and Methods Eleven obese and 7 nonobese individuals with T2DM participated in this randomized, placebo-controlled, double-blind, crossover study. Each subject underwent a pair of “stepped” pancreatic clamp studies with subcutaneous adipose tissue biopsies after 21 days of pioglitazone (45 mg) or placebo. Results Obese subjects demonstrated significant decreases in insulin resistance and many adipose inflammatory parameters with pioglitazone relative to placebo. Specifically, significant improvements in glucose infusion rates, suppression of hepatic glucose production, and whole fat expression of certain inflammatory markers (IL-6, IL-1B, and inducible nitric oxide synthase) were observed in the obese subjects but not in the nonobese subjects. Additionally, adipose tissue from the obese subjects demonstrated reduced infiltration of macrophages, dendritic cells, and neutrophils as well as increased expression of factors associated with fat “browning” (peroxisome proliferator–activated receptor gamma coactivator-1α and uncoupling protein-1). Conclusions These findings support the efficacy of pioglitazone to improve insulin resistance and reduce adipose tissue inflammation in obese patients with T2DM.

Coordinated Regulation of Adipose Tissue Macrophages by Cellular and Nutritional Signals

The current epidemic of obesity is fueling a global rise in non-communicable diseases, including type 2 diabetes mellitus, atherothrombotic disease, and cancer. Obesity is associated with systemic inflammation, with various fat-derived inflammatory factors being implicated in the pathophysiology of insulin resistance. The infiltration of various types of inflammatory cells into adipose tissue seems to be an important mechanism whereby nutrient excess contributes to systemic insulin resistance. In particular, adipose tissue macrophages are abundant in obese adipose tissue, and may be the source of the majority of fat-derived circulating inflammatory factors. This review examines recent studies exploring mechanisms whereby cellular and nutritional signals mediate macrophage recruitment to adipose tissue and their pro-inflammatory activation.

Surrogate measures of insulin sensitivity when compared to euglycemic hyperinsulinemic clamp studies in Asian Indian men without diabetes

AIM Fasting surrogate measures of insulin sensitivity are increasingly used in research and clinical practice. To assess the reliability of these measures, we aimed to evaluate multiple fasting surrogate measures simultaneously in non-diabetic subjects in comparison with the euglycemic hyperinsulinemic clamp study. METHODS Sixteen normoglycemic male South Indian subjects were studied. After an overnight fast, blood samples were collected for glucose, insulin and lipid profile measurements, and stepped euglycemic hyperinsulinemic clamp studies were performed on all subjects. Steady state glucose infusion rates (M value) during low and high insulin phases of the clamp were calculated. Correlation of M value with surrogate markers of insulin sensitivity was performed. Predictive accuracy of surrogate indices was measured in terms of Root Mean Squared Error (RMSE) and leave-one-out cross-validation-type RMSE of prediction using a calibration model. RESULTS M values showed a strong and significant correlation (p<0.01) with the following surrogate markers: Fasting insulin (r=-0.714), Fasting glucose to insulin ratio (FGIR, r=0.747) and Raynaud index (r=0.714). FGIR had a significantly lower RMSE when compared with HOMA-IR and QUICKI. CONCLUSIONS Among the surrogate measures, FGIR had the strongest correlation with M values. FGIR was also the most accurate surrogate measure, as assessed by the calibration model.

Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes.

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 μg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ∼30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF’s development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Potential approaches to prevent hypoglycemia-associated autonomic failure

Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to ‘hypoglycemia-associated autonomic failure’ (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.