Kashif M. Munir

Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications.

The rising epidemic of diabetes is a pressing issue in clinical medicine worldwide from both healthcare and economic perspectives. This is fueled by overwhelming increases in the incidence and prevalence of obesity. Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality. Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications. Therefore, therapeutic approaches that target either insulin resistance or endothelial dysfunction alone are likely to simultaneously improve both metabolic and cardiovascular pathophysiology and disease outcomes. Moreover, combination therapies with agents targeting distinct mechanisms are likely to have additive or synergistic benefits. Conventional therapies for diabetes and its cardiovascular complications that are both safe and effective are insufficient to meet rising demand. Large, robust, epidemiologic studies demonstrate beneficial metabolic and cardiovascular health effects for many functional foods containing various polyphenols. However, precise molecular mechanisms of action for food polyphenols are largely unknown. Moreover, translation of these insights into effective clinical therapies has not been fully realized. Nevertheless, some functional foods are likely sources for safe and effective therapies and preventative strategies for metabolic diseases and their cardiovascular complications. In this review, we emphasize recent progress in elucidating molecular, cellular, and physiological actions of polyphenols from green tea (EGCG), cocoa (ECG), and citrus fruits (hesperedin) that are related to improving metabolic and cardiovascular pathophysiology. We also discuss a rigorous comprehensive approach to studying functional foods that is essential for developing novel, effective, and safe medications derived from functional foods that will complement existing conventional drugs.

Two Cases Of Thyroid Storm-Associated Cholestatic Jaundice

OBJECTIVE To describe the association of the rare and serious complication of jaundice with severe thyrotoxicosis, a potentially lethal endocrine disorder. METHODS We report the clinical, laboratory, and pathologic findings of 2 cases of severe jaundice (total bilirubin levels: 35.2 mg/dL in case 1 and 42 mg/dL in case 2) associated with thyroid storm in the absence of a history of liver disease, thionamide exposure, or congestive heart failure. We also present other relevant reports available in the literature. RESULTS Case 1 was a 38-year-old woman who presented with nausea, vomiting, fatigue, pruritus, and frequent nonbloody diarrhea. She was transferred to our institution because of worsening hyperbilirubinemia. Case 2 was a 35-year-old woman admitted to a community hospital with thyroid storm and jaundice. Upon transfer to our institution, the patient was unconscious, mechanically ventilated, and in atrial fibrillation. In case 2, liver biopsy results revealed diffuse hepatocellular ballooning with intrahepatic cholestasis with mild portal lymphocytic infiltration. Both patients presented with severe cholestatic jaundice in the absence of congestive heart failure; underlying liver disease (infectious or autoimmune); or previous exposure to thionamides, other hepatotoxic agents, or complementary and alternative medications. In both cases, jaundice responded to therapy with antithyroid medications. Both patients eventually underwent thyroidectomy with complete resolution of the jaundice. CONCLUSION The data strongly suggest that in these patients, the hepatic dysfunction was primarily due to hyperthyroidism. These cases indicate that the mere presence of hyperbilirubinemia during severe thyrotoxicosis should not per se delay the use of potentially life-saving thionamides once a thorough evaluation for other causes of liver disease has been completed.

Vascular and Metabolic Actions of the Green Tea Polyphenol Epigallocatechin Gallate

Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin-mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations.

New progress in adipocytokine research

Purpose of reviewThe purpose of this review is to discuss newly identified adipocyte-derived signaling molecules—adipocytokines—and to provide our current understanding of the mechanisms through which these factors regulate energy homeostasis. Recent findingsAdipose tissue was long known to secrete bioactive substances from fatty acids to steroid hormones. Recent research has disclosed a group of cytokine or cytokine-like molecules such as leptin, tumor necrosis factor-&agr; (TNF-&agr;), interleukin-6 (IL-6), adiponectin, resistin, and PPAR-&ggr;–regulated angiopoietin-related protein (PGAR), among others. These factors play a central role in how the adipocyte communicates with a variety of tissues and allow the adipocyte to sense its own energy stores and to control its own mass. Major recent developments include 1) the identification of AMP-activated protein kinase (AMPK) as a target molecule through which leptin acts in peripheral tissues to induce fat oxidation and reduce lipogenesis, and which mediates leptins antiosteogenic effect; 2) functional characterization of adiponectin in vivo and in vitro as an insulin sensitizer, in part through activation of AMPK; 3) the understanding that in contrast to prevailing views, the overall effect of IL-6 is protective against obesity, as demonstrated in IL-6 knockout mice; and 4) the insight that PGAR is potentially an important molecule that regulates lipid metabolism. SummaryAdipose tissue, as endocrine tissue, secretes a wide range of bioactive substances. Challenges ahead are to define their physiologic roles and to determine to what extent they contribute to pathophysiologic conditions such as obesity, insulin resistance, and type 2 diabetes.

Genetics of obesity: More complicated than initially thought

During the past several decades, there has been an explosion in the prevalence of obesity. Since our genes have not changed appreciably during that time, it stands to reason that the present epidemic is caused by our pervasive obesigenic environment, in which excess caloric intake and decreased physical activity conspire with one another. Despite an obesigenic environment, humans have great variability in their susceptibility to obesity, which is determined in large part by genetics. Current evidence suggests that genetic susceptibility to human obesity is the result of multiple genes, each with a modest effect, that interact with each other and with environmental provocations. Elucidation of obesity susceptibility genes through genome-wide and candidate gene approaches provides great promise in ultimately determining the genetic underpinnings of obesity. Further research will translate these new insights on the pathophysiological basis of obesity into new medications and diagnostic tests.

Coronary artery calcification in patients with primary hyperparathyroidism in comparison with control subjects from the multi-ethnic study of atherosclerosis.

OBJECTIVE To determine whether coronary artery calcification (CAC) is increased in patients with primary hyperparathyroidism (pHPT) because of the presence of hypercalcemia, which has been shown in vitro to promote vascular calcification. METHODS Electron beam computed tomography of the coronary arteries was performed on 20 patients with pHPT referred to our endocrinology clinic for evaluation of hypercalcemia. All patients were nonsmokers, with normal renal function, no history of diabetes, and no history of coronary artery disease. CAC in the patients with pHPT was compared with that in population-based control subjects from the Multi-Ethnic Study of Atherosclerosis (MESA). Two methods of analysis were used: (1) calculation of the odds ratio of CAC and (2) a nested case-control (1:4) study. RESULTS One patient with pHPT had a history of nephrolithiasis; the other 19 patients were asymptomatic. The mean age (+/- SD) of the patients with pHPT was 57.3 +/- 9.1 years, the mean serum calcium concentration was 2.68 +/- 0.18 mmol/L, and the mean intact parathyroid hormone level was 119 +/- 76.5 pg/mL. Of the 20 patients, 14 had CAC scores of zero. The odds ratio for measurable CAC in the presence of pHPT in comparison with that in the MESA control subjects was 0.17, which was not significant. In the matched analysis, the CAC scores for the patients with pHPT did not differ significantly from those for the MESA control subjects (P = 0.25 with use of the Wilcoxon test). CONCLUSION We found no evidence for a difference in CAC in patients with pHPT in comparison with the population-based control subjects in this small pilot study.

The treatment of type 1 diabetes mellitus with agents approved for type 2 diabetes mellitus

Introduction: The management of type 1 diabetes remains a challenge for clinicians. Current practice is to administer insulin analogues to best mimic normal physiological insulin profiles. However, despite our best efforts the majority of individuals with type 1 diabetes continue to suffer from suboptimal glucose control, significant hypoglycemia and microvascular tissue complications of the disease. There is thus a significant unmet need in the treatment of T1DM to obtain better glycemic control. Areas covered: We discuss the use of α-glucosidase inhibitors, dipeptidyl-peptidase inhibitors, glucagon-like peptide 1 agonists, biguanides, thiazolidinediones and sodium glucose co-transporter 2 inhibitors in individuals with T1DM. Expert opinion: Non-insulin therapies present a unique and exciting adjunctive treatment for individuals with type 1 diabetes. Although data are scarce, the classes of medications discussed help to lower glucose, decrease glycemic excursions and in some cases improve body weight, along with allowing dose reductions in total daily insulin. Glucagon-like peptide 1 agonists and sodium glucose co-transporter 2 inhibitors, in particular, have been demonstrated to provide clinical improvements in individuals with T1DM and we feel their use can be explored in obese, insulin-resistant patients with T1DM, those with frequent and significant glycemic excursions or individuals with persistently elevated hemoglobin A1c.

Diabetes type 2 management: what are the differences between DPP-4 inhibitors and how do you choose?

Type 2 diabetes mellitus (T2DM) is characterized by progressive beta cell dysfunction and insulin resistance. Pharmacotherapy to treat dysregulated glucose metabolism focuses on augmenting the insulin response to hyperglycemia, improving insulin sensitivity or altering glucose disposal through the gut or urine. Dipeptidyl-peptidase-4 (DPP-4) inhibitors or ‘gliptins’ block the inactivation of glucagon-like peptide-1 (GLP-1), which stimulates glucose-dependent insulin secretion and inhibits glucagon secretion. Additionally, gastric emptying is slowed, satiety is improved, and food intake is reduced [1]. These effects are more prominent with use of GLP-1 receptor agonists. There are five DPP-4 inhibitors, including alogliptin, linagliptin, saxagliptin, and sitagliptin in the United States and Europe and vildagliptin which is only available in Europe (Table 1). This class of anti-hyperglycemic therapy is orally administered once per day with the exception of vildagliptin which is dosed twice per day. DPP-4 inhibitors can be taken without regard to food. DPP-4 inhibitors are not recommended for use as initial monotherapy for T2DM treatment [3]. They are most commonly prescribed in combination with lifestyle modification and metformin, sulfonylureas, thiazolidinediones, and/or basal insulin, but select patients intolerant to metformin have been successfully treated with DPP-4 inhibitor monotherapy. There are a number of combination products available, including gliptin–metformin and gliptin–sodium glucose transporter-2 inhibitor products. There is a paucity of direct head-to-head studies of DPP-4 inhibitors. Most comparisons are indirect. Evaluation of singular beneficial effects have been published, such as effects on cholesterol, and attributed to one particular drug within the class; however, it is reasonable to consider that these effects may be applicable across the class of medications.

Differential pharmacology and clinical utility of empagliflozin in type 2 diabetes.

With rates of obesity and diabetes rising across the world, effective therapies to treat hyperglycemia and its associated comorbidities continue to be in demand. Empagliflozin is a highly selective sodium glucose transporter-2 inhibitor that improves serum glucose levels by inducing glucosuria. Taken orally, it is rapidly absorbed with linear pharmacokinetics consistent in Asian and Caucasian populations. Empagliflozin treatment demonstrates consistent reductions in hemoglobin A1c, fasting plasma glucose, body weight, and blood pressure in individuals with type 2 diabetes. Improvements in glycemic control and metabolic end points are evident with empagliflozin monotherapy, as add-on to oral hypoglycemics or add-on to insulin. The nonglycemic effects of empagliflozin with consistent improvements in blood pressure, body weight, and waist circumference provide additional rationale for use in patients with type 2 diabetes. Moreover, treatment with empagliflozin has recently shown significant reductions in both microvascular and macrovascular complications of diabetes.

Reninoma Presenting in Pregnancy

23-year-old Caucasian female was diagnosed with hypertension and controlled with an angiotensinconverting enzyme inhibitor and a beta-blocker. Two years later, she developed hypokalemia. She had normal urineandplasmacatecholaminesandmetanephrines,and aldosterone was appropriately suppressed in a saline suppression test. Computed tomography angiogram (CTA) andmagneticresonanceangiographydidnotdetectstructural renal or adrenal causes. She then became pregnant; theangiotensin-convertingenzymeinhibitorwaschanged to a calcium channel blocker and methyldopa, without however maintaining adequate control. At 26 weeks of pregnancy, she underwent cesarean section for hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome);thenewborninfantdiedaftera4-weekcomplicated course in intensive care. The patient was referred later to the National Institutes of Health for uncontrolled hypertension. Her upright plasma renin activity was 20 ng/mL/h (normal, 4.3), and her aldosterone level was 110 ng/dL (normal,21). CTA, magnetic resonance angiography, positron emission tomography, and renal venous sampling established the diagnosis of a 1-cm left kidney renin-secreting lesion (Figure 1, A–C and E). Her blood pressure normalized immediately after a left partial nephrectomy. Histopathology was consistent with a juxtaglomerular cell tu