There is wide variance among individuals in the fraction of insulin cleared by the liver (20% to 80%). Hepatic insulin clearance is 67% lower in African Americans than European Americans. Clearance ...is also lower in African American children 7-13 years of age. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia: this exacerbates insulin resistance, which stresses the β-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lower insulin clearance can be a primary cause of type 2 diabetes in at-risk individuals.
Most of the literature related to high altitude medicine is devoted to the short-term effects of high-altitude exposure on human physiology. However, long-term effects of living at high altitudes may ...be more important in relation to human disease because more than 400 million people worldwide reside above 1500 m. Interestingly, individuals living at higher altitudes have a lower fasting glycemia and better glucose tolerance compared with those who live near sea level. There is also emerging evidence of the lower prevalence of both obesity and diabetes at higher altitudes. The mechanisms underlying improved glucose control at higher altitudes remain unclear. In this review, we present the most current evidence about glucose homeostasis in residents living above 1500 m and discuss possible mechanisms that could explain the lower fasting glycemia and lower prevalence of obesity and diabetes in this population. Understanding the mechanisms that regulate and maintain the lower fasting glycemia in individuals who live at higher altitudes could lead to new therapeutics for impaired glucose homeostasis.
BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
The Physiology of Insulin Clearance Bergman, Richard N; Kabir, Morvarid; Ader, Marilyn
International journal of molecular sciences,
02/2022, Letnik:
23, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In the 1950's, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, ...insulin degradation is now being recognized as a possible factor in diabetes risk. After Mirsky, the relative importance of defects in insulin release and insulin resistance were recognized as risk factors. The hyperbolic relationship between secretion and sensitivity was introduced, as was the relationship between them, as expressed as the disposition index (DI). The DI was shown to be affected by environmental and genetic factors, and it was shown to be differentiated among ethnic groups. However, the importance of differences in insulin degradation (clearance) on the disposition index relationship remains to be clarified. Direct measure of insulin clearance revealed it to be highly variable among even normal individuals, and to be affected by fat feeding and other physiologic factors. Insulin clearance is relatively lower in ethnic groups at high risk for diabetes such as African Americans and Hispanic Americans, compared to European Americans. These differences exist even for young children. Two possible mechanisms have been proposed for the importance of insulin clearance for diabetes risk: in one concept, insulin resistance per se leads to reduced clearance and diabetes risk. In a second and new concept, reduced degradation is a primary factor leading to diabetes risk, such that lower clearance (resulting from genetics or environment) leads to systemic hyperinsulinemia, insulin resistance, and beta-cell stress. Recent data by Chang and colleagues appear to support this latter hypothesis in Native Americans. The importance of insulin clearance as a risk factor for metabolic disease is becoming recognized and may be treatable.
Abstract Visceral adiposity has been identified as an independent risk factor for cardiovascular disease and the so-called metabolic syndrome. The canine obesity model closely recapitulates the ...correlation between human visceral adiposity and insulin resistance. A recent canine study indicates that insulin expands the volume of distribution associated with skeletal muscle, and that its ability to enhance macromolecular distribution within this space is blunted in the fat-fed obese canine model. Our canine study supports the portal theory of insulin resistance, in which free fatty acids (FFAs) from visceral fat directly enter the liver and have a detrimental effect on insulin action. The role of adipokines in this condition remains less clear. Sympathetic nervous system hyperactivity in obesity may also contribute to excessive FFA release, hypertension, and insulin resistance. Pathologies interrelated with insulin resistance include β-cell hypersecretion, reduced insulin clearance, and resultant hyperinsulinemia. An observed nocturnal increase in plasma FFA levels may account for both insulin resistance and compensatory hyperinsulinemia and warrants further investigation. The elucidation of these interrelated pathologies may help reveal points where medical intervention can reduce metabolic disease.
Objective
Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than ...obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions.
Methods
Metabolic assessment was performed in healthy dogs (n = 90). Whole‐body sensitivity from euglycemic clamps (SICLAMP) was the primary outcome variable, and was measured independently by IVGTT (n = 36). Adiposity was measured by MRI (n = 90), and glucose‐stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n = 86 and 36, respectively).
Results
SICLAMP was highly variable (5.9‐75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight‐fold and was inversely correlated with SICLAMP (P < 0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r = 0.53, P < 0.00001), whether calculated from clamp or IVGTT.
Conclusions
These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.
Metabolic Dysregulation With Atypical Antipsychotics Occurs in the Absence of Underlying Disease A Placebo-Controlled Study
of Olanzapine and Risperidone in Dogs
Marilyn Ader ,
Stella P. Kim ,
Karyn ...J. Catalano ,
Viorica Ionut ,
Katrin Hucking ,
Joyce M. Richey ,
Morvarid Kabir and
Richard N. Bergman
From the Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles,
California
Address correspondence and reprint requests to Marilyn Ader, PhD, Keck School of Medicine, Department of Physiology and Biophysics,
University of Southern California, MMR 624, 1333 San Pablo St., Los Angeles, CA 90033. E-mail: ader{at}hsc.usc.edu
Abstract
Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical
antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S I ), and pancreatic β-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n = 10), RIS (5 mg/day; n = 10), or gelatin capsules ( n = 6) for 4–6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (+91 ± 20%; P = 0.000001) reflecting marked increases in subcutaneous (+106 ± 24%; P = 0.0001) and visceral (+84 ± 22%; P = 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group ( P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S I pre- versus postdrug: 6.05 ± 0.98 vs. 1.53 ± 0.93 dl · min −1 · kg −1 /μU/ml, respectively; P = 0.009). β-Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 ± 0.15, post-drug: 1.07 ± 0.25 μU · ml −1 /mg/dl; P = 0.6). OLZ-induced β-cell dysfunction was further demonstrated when β-cell compensation was compared with a group of animals
with adiposity and insulin resistance induced by moderate fat feeding alone (+8% of calories from fat; n = 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that β-cell compensation
is under neural control.
DI, disposition index
EGC, euglycemic-hyperinsulinemic clamp
FFA, free fatty acid
HGO, hepatic glucose output
MRI, magnetic resonance imaging
OLZ, olanzapine
RIS, risperidone
Footnotes
M.A. has received honoraria from Janssen Pharmaceutica. R.N.B. has served on an advisory panel for and received consulting
fees from Janssen Pharmaceutica.
Accepted November 29, 2004.
Received July 6, 2004.
DIABETES
Background: Most glucokinase (GCK) in the body is found in the liver, where it serves as a glucose sensor and gatekeeper, determining the rate of glycolysis. Mutations in GCK are a cause of ...maturity-onset diabetes of the young, and glucokinase regulatory protein (GCKR), the regulator of hepatic GCK, is also a diabetes susceptibility locus. Recently we utilized lactate export by the liver as a surrogate for glucokinase activity in vivo, which was a measure of "glucose effectiveness". We hypothesized that in vitro GCK suppression in hepatocytes simulates a reduction in lactate production via glycolysis. Methods: We "knock downed" GCK via lipid delivery of siRNA in dog cryopreserved hepatocytes. Results: Selective blocking of GCK by specific siRNA did not change cell proliferation after 48h of culture. However, GCK gene expression was reduced by 90 %. GCK knockdown reduced lactate secreted into the medium by 50% and 43% after 24 h and 48 h of hepatocyte culture, respectively. Conclusions: These observations provide experimental evidence supporting the use of lactate production as a surrogate for glucokinase activity. The direct suppression of GCK by antisense oligonucleotides or CRISPR gene-editing approaches in animals will be useful tools in vivo to evaluate the glucose-lactate relationship and the role of glucose effectiveness in the pathogenesis of type 2 diabetes.
Glucokinase (GCK) mediates hepatic glucose uptake during hyperglycemia and is crucial for the regulation of glucose-responsive glycolysis genes. Mutations in GCK are responsible for maturity-onset ...diabetes of the young, and glucokinase regulatory protein (GKRP) , the regulator of hepatic GCK, is also a diabetes susceptibility locus. Recently in in vivo experiments, we used hepatic lactate export as a surrogate for GCK activity, which was a measure of “glucose effectiveness.” We hypothesized that in vitro GCK and GKRP suppression in hepatocytes promotes a reduction in lactate and pyruvate export from the liver. We used cryopreserved canine hepatocytes and knocked down GCK and GKRP via lipid delivery of siRNA. A control group did not receive siRNA. We measured lactate dehydrogenase D (LDHD) and pyruvate kinase (PK) gene expression and lactate and pyruvate release into the medium 24 and 48 h after siRNA delivery. Selective blocking of GCK and GKRP did not change cell proliferation but reduced the expression of these genes by 90% and 85%, respectively (P<0.0vs. controls; n=4) . GCK and GKRP knockdown reduced LDHD by 71% and 74%, respectively (P<0.001) ; similarly, PK was reduced by 84% and 82%, respectively (P<0.001) . Lactate exported into the medium was reduced by 36% (P<0.001) and 26% (P<0.05) by GCK and GKRP siRNA, respectively, after 48 h of hepatocyte culture. However, pyruvate was reduced by 17% only after 48 h culture of GCK siRNA (P<0.05) . Thus, we showed that direct suppression of GCK and GKRP genes by siRNA in vitro affects glucose-responsive glycolysis genes, consequently reducing lactate export which can be used as a surrogate for reduced glucokinase activity in hepatocytes. The use of antisense oligonucleotides or CRISPR gene-editing methods in animals will be useful methods to study the glucose-lactate relationship in vivo and will evaluate the role of glucose effectiveness in the pathogenesis of type 2 diabetes.
Disclosure
M.Kabir: None. M.Ader: None. R.N.Bergman: Consultant; Fractyl Health, Inc., Novo Nordisk, Research Support; AstraZeneca, Janssen Research & Development, LLC.
Funding
National Institutes of Health R01- DK027619-28
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