Insulin Clearance in Obesity and Type 2 Diabetes

Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.

Fluidics system for resolving concentration-dependent effects of dissolved gases on tissue metabolism

Oxygen (O2) and other dissolved gases such as the gasotransmitters H2S, CO and NO affect cell metabolism and function. To evaluate effects of dissolved gases on processes in tissue, we developed a fluidics system that controls dissolved gases while simultaneously measuring parameters of electron transport, metabolism and secretory function. We use pancreatic islets, retina and liver from rodents to highlight its ability to assess effects of O2 and H2S. Protocols aimed at emulating hypoxia-reperfusion conditions resolved a previously unrecognized transient spike in O2 consumption rate (OCR) following replenishment of O2, and tissue-specific recovery of OCR following hypoxia. The system revealed both inhibitory and stimulatory effects of H2S on insulin secretion rate from isolated islets. The unique ability of this new system to quantify metabolic state and cell function in response to precise changes in dissolved gases provides a powerful platform for cell physiologists to study a wide range of disease states.

Fluidics System for Resolving Concentration-Dependent Effects of Dissolved Gases on Tissue Metabolism

ABSTRACTOxygen (O2) and other dissolved gases such as the gasotransmitters H2S, CO and NO affect cell metabolism and function. To evaluate effects of dissolved gases on processes in tissue, we developed a fluidics system that controls dissolved gases while simultaneously measuring parameters of electron transport, metabolism and secretory function. We use pancreatic islets, retina and liver to highlight its ability to assess effects of O2 and H2S. Protocols aimed at emulating hypoxia-reperfusion conditions resolved a previously unrecognized transient spike in O2 consumption rate (OCR) following replenishment of O2, and tissue-specific recovery of OCR following hypoxia. The system revealed both inhibitory and stimulatory effects of H2S on insulin secretion rate from isolated islets. The unique ability of this new system to quantify metabolic state and cell function in response to precise changes in dissolved gases provides a powerful platform for cell physiologists to study a wide range of disease states.

Deficiency of Urokinase Plasminogen Activator May Impair β Cells Regeneration and Insulin Secretion in Type 2 Diabetes Mellitus

: Background: The relationship between urokinase-type plasminogen activator (uPA) and the development of type 2 diabetes mellitus (T2DM) was investigated in the study by using mice and cell models, as well as patients with T2DM. Methods: In mice models, wild-type and uPA knockout (uPA-/-) BALB/c mice were used for induction of T2DM. In cell models, insulin secretion rate and β cell proliferation were assessed in normal and high glucose after treating uPA siRNA, uPA, or anti-uPA antibody. In our clinical study, patients with T2DM received an oral glucose-tolerance test, and the relationship between uPA and insulin secretion was assessed. Results: Insulin particles and insulin secretion were mildly restored one month after induction in wild-type mice, but not in uPA-/- mice. In cell models, insulin secretion rate and cell proliferation declined in high glucose after uPA silencing either by siRNA or by anti-uPA antibody. After treatment with uPA, β cell proliferation increased in normal glucose. In clinical study, patients with T2DM and higher uPA levels had better ability of insulin secretion than those with lower uPA levels. Conclusion: uPA may play a substantial role in insulin secretion, β cell regeneration, and progressive development of T2DM. Supplementation of uPA might be a novel approach for prevention and treatment of T2DM in the future.

Visceral adipose tissue tracks more closely with metabolic dysfunction than intrahepatic triglyceride in lean Asians without diabetes

Increased visceral adipose tissue (VAT) and intrahepatic triglyceride (IHTG) are important risk factors for the development of type 2 diabetes in subjects with obesity. The relative contribution of these ectopic fat depots to cardiometabolic risk differs between populations, depends on the degree of obesity and the level of cardiorespiratory fitness, and is difficult to dissect because VAT and IHTG typically covary. The aim of this study was to evaluate the effect of an isolated increase in VAT or IHTG on insulin sensitivity and insulin secretion in apparently healthy normal-weight Asian subjects. Total body fat (dual X-ray absorptiometry), VAT and IHTG (magnetic resonance), insulin sensitivity (4-h hyperinsulinemic-euglycemic clamp), beta cell responsivity and insulin secretion rate (3-h mixed meal with mathematical modeling), and cardiorespiratory fitness (maximal oxygen consumption [V̇o2max]) were evaluated in groups of lean subjects with low or high VAT (687 ± 94 vs. 1,279 ± 197 ml, matched for IHTG; n = 13 each) and low or high IHTG (1.7 ± 0.3 vs. 6.7 ± 2.0%, matched for VAT; n = 15 each). All groups were matched for age, sex, total body fat, and V̇o2max. High-VAT subjects had ~25% lower insulin sensitivity, ~20%–40% greater beta cell responsivity and insulin secretion rate, ~35% greater fasting triglyceride concentration, and ~40% lower adiponectin concentration than low-VAT subjects (all P < 0.05). No differences were observed between low-IHTG and high-IHTG subjects. Accumulation of excess fat in the intra-abdominal area is more strongly associated with metabolic dysfunction than accumulation of liver fat in lean Asians without diabetes. NEW & NOTEWORTHY It is not known whether metabolic abnormalities in Asians without obesity track more closely with visceral or liver fat. We found an isolated increase in visceral fat was associated with reduced insulin sensitivity, greater insulin secretion, greater triglyceride, and lower adiponectin concentrations; no differences were observed with an isolated increase in liver fat. These results suggest that visceral fat is a better correlate of metabolic dysfunction than liver fat in Asians without obesity.

Insulin clearance: an underappreciated modulator of plasma insulin concentration

Plasma glucose concentrations are tightly regulated and maintained within a narrow range in non-diabetic individuals. Maintenance of this physiological state is primarily a function of the ability of the pancreatic β-cells to modify insulin secretion rate (ISR), thus preventing wide-swings in plasma glucose concentrations. As a consequence, and in contrast to plasma glucose concentrations, plasma insulin concentrations vary substantially in non-diabetic individuals. Although differences in ISR are primarily responsible for the variability in plasma insulin concentration, there is increasing evidence that differences in insulin clearance rate (ICR) also play a role in regulation of plasma insulin concentration. The goal of this mini-review is to highlight situations that demonstrate the important role of ICR in both insulin and glucose homeostasis.

A highly energetic process couples calcium influx through L-type calcium channels to insulin secretion in pancreatic β-cells

Calcium (Ca2+) influx is required for the sustained secretion of insulin and is accompanied by a large rate of energy usage. We hypothesize that the energy usage reflects a process [Ca2+/metabolic coupling process (CMCP)] that couples Ca2+ to insulin secretion by pancreatic islets. The aim of the study was to test this hypothesis by testing the effect of inhibiting candidate Ca2+-sensitive proteins proposed to play a critical role in the CMCP. The effects of the inhibitors on oxygen consumption rate (OCR), a reflection of ATP usage, and insulin secretion rate (ISR) were compared with those seen when L-type Ca2+ channels were blocked with nimodipine. We reasoned that if a downstream Ca2+-regulated site was responsible for the OCR associated with the CMCP, then its inhibition should mimic the effect of nimodipine. Consistent with previous findings, nimodipine decreased glucose-stimulated OCR by 36% and cytosolic Ca2+ by 46% and completely suppressed ISR in rat pancreatic islets. Inhibitors of three calmodulin-sensitive proteins (myosin light-chain kinase, calcineurin, and Ca2+/calmodulin-dependent protein kinase II) did not meet the criteria. In contrast, KN-62 severed the connection between Ca2+ influx, OCR, and ISR without interfering with Ca2+ influx. In the presence of nimodipine or KN-62, potentiators of ISR, acetylcholine, GLP-1, and arginine had little effect on insulin secretion, suggesting that the CMCP is also essential for the amplification of ISR. In conclusion, a KN-62-sensitive process directly mediates the effects of Ca2+ influx via L-type Ca2+ channels on OCR and ISR, supporting the essential role of the CMCP in mediating ISR.