Rebecca L. Paszkiewicz

Insulin access to skeletal muscle is impaired during the early stages of diet-induced obesity

Insulin must move from the blood to the interstitium to initiate signaling, yet access to the interstitium may be impaired in cases of insulin resistance, such as obesity. This study investigated whether consuming a short‐ and long‐term high‐fat diet (HFD) impairs insulin access to skeletal muscle, the major site of insulin‐mediated glucose uptake.

Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity

Aims/hypothesisThe worldwide incidence of obesity and diabetes continues to rise at an alarming rate. A major cause of the morbidity and mortality associated with obesity and diabetes is heart disease, yet the mechanisms that lead to cardiovascular complications remain unclear.MethodsWe performed cardiac MRI to assess left ventricular morphology and function during the development of moderate obesity and insulin resistance in a well-established canine model (n = 26). To assess the influence of dietary fat composition, we randomised animals to a traditional lard diet (rich in saturated and monounsaturated fat; n = 12), a salmon oil diet (rich in polyunsaturated fat; n = 8) or a control diet (n = 6).ResultsHigh-fat feeding with lard increased body weight and fasting insulin and markedly reduced insulin sensitivity. Lard feeding also significantly reduced left ventricular function, evidenced by a worsening of circumferential strain and impairment in left ventricular torsion. High-fat feeding with salmon oil increased body weight; however, salmon oil feeding did not impair insulin sensitivity or cardiac function.Conclusions/interpretationThese data emphasise the importance of dietary fat composition on both metabolic and cardiac function, and have important implications for the relationship between diet and health.

Increase in visceral fat per se does not induce insulin resistance in the canine model

To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance.

Insulin Access to Skeletal Muscle is Preserved in Obesity Induced by Polyunsaturated Diet: Insulin Access to Muscle in Diet-Induced Obesity

Diets high in saturated fat induce obesity and insulin resistance and impair insulin access to skeletal muscle, leading to reduced insulin levels at the muscle cell surface available to bind insulin receptors and induce glucose uptake. In contrast, diets supplemented with polyunsaturated fat improve insulin sensitivity (SI) and reduce the risk for type 2 diabetes. It was hypothesized that a diet high in polyunsaturated fat would preserve SI and insulin access to muscle, as compared with a diet high in saturated fat.

Variability of Directly Measured First-Pass Hepatic Insulin Extraction and Its Association With Insulin Sensitivity and Plasma Insulin

Although the β-cells secrete insulin, the liver, with its first-pass insulin extraction (FPE), regulates the amount of insulin allowed into circulation for action on target tissues. The metabolic clearance rate of insulin, of which FPE is the dominant component, is a major determinant of insulin sensitivity (SI). We studied the intricate relationship among FPE, SI, and fasting insulin. We used a direct method of measuring FPE, the paired portal/peripheral infusion protocol, where insulin is infused stepwise through either the portal vein or a peripheral vein in healthy young dogs (n = 12). FPE is calculated as the difference in clearance rates (slope of infusion rate vs. steady insulin plot) between the paired experiments. Significant correlations were found between FPE and clamp-assessed SI (rs = 0.74), FPE and fasting insulin (rs = −0.64), and SI and fasting insulin (rs = −0.67). We also found a wide variance in FPE (22.4–77.2%; mean ± SD 50.4 ± 19.1) that is reflected in the variability of plasma insulin (48.1 ± 30.9 pmol/L) and SI (9.4 ± 5.8 × 104 dL · kg−1 · min−1 · [pmol/L]−1). FPE could be the nexus of regulation of both plasma insulin and SI.

Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement

Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min-1) and FPE (%). In contrast, we observed a poor association between MCR (ml·min-1·kg-1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE.

Mechanisms of improved glucose handling after metabolic surgery: the big 6

For some time, it has been clear that elevated glucose is detrimental to the organism. A plethora of medicines have been introduced to reduce the fasting and postprandial glucose levels (including insulin, glucagon-like peptide receptor 1 [GLP-1] agonists, and sodium-glucose co-transporter 2 [SGLT2] inhibitors, among others). Although these medications are useful to reduce tissue exposure to glucose, no single compound and no combination have been able to totally normalize the blood sugar. Thus, it was astonishing when it was reported that surgery of the gastrointestinal tract could not only reduce obesity but also normalize the blood sugar. These discoveries have transformed diabetes research. What is it about bariatric surgery that causes the remarkable amelioration of glucose homeostasis dysregulation? The answer to this million dollar question is a billion dollar answer. However, a new perspective could shed some light and help provide a clear path for investigation. Instead of asking what does bariatric surgery do to change the pathophysiology, we can ask what pathophysiology and risk factors confer a greater success with remission and improved disease state after surgery. Work from our laboratory and others can help to offer a physiologic basis for which mechanisms may be put into play when the anatomy is altered during surgery. Here, we do not offer an explanation of the mechanism of action of bariatric surgery, but rather provide a background on the regulation of blood glucose and how it is altered during both the diseased state and, as available, the remission state.