Systemic benefits of Gc inhibition to preserve insulin sensitivity

Mapping Intimacies ◽

10.1101/2020.10.06.328963 ◽

2020 ◽

Author(s):

Taiyi Kuo ◽

Domenico Accili

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Cell Function ◽

Hepatic Glucose Production ◽

Glucose Production ◽

High Fat ◽

Β Cell ◽

Hepatic Glucose ◽

Β Cell Function

ABSTRACTType 2 diabetes is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired β-cell function contribute to the onset of hyperglycemia. No single treatment modality can affect both aspects of diabetes pathophysiology. Thus, current treatments focus either on increasing insulin secretion (incretin mimetics, sulfonylureas) or insulin sensitivity (metformin and TZD), or reducing hyperglycemia (insulin, sglt2i). Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic β-cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin’s ability to reduce hepatic glucose production, and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in β-cells, and insulin action in peripheral tissues.RESEARCH IN CONTEXT▪ The goal was to find a therapeutic target that can improve insulin sensitivity and β-cell function simultaneously.▪ Gc ablation preserves β-cell insulin secretion ex vivo and in vivo.▪ Deletion of Gc prevents weight gain, reduces fat mass, lowers fasting glycemia, improves glucose tolerance, reduces hepatic glucose production after feeding, and increased glucose uptake in muscle and adipose.▪ Acute Gc inhibition improves glucose tolerance, which suggests that targeting Gc could provide an alternative way to treat type 2 diabetes.

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Common Risk Factors in Relatives and Spouses of Patients with Type 2 Diabetes in Developing Prediabetes

Healthcare ◽

10.3390/healthcare9081010 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1010

Author(s):

Wei-Hao Hsu ◽

Chin-Wei Tseng ◽

Yu-Ting Huang ◽

Ching-Chao Liang ◽

Mei-Yueh Lee ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Cell Function ◽

Diabetic Patients ◽

Β Cell ◽

Tyg Index ◽

Β Cell Function

Prediabetes should be viewed as an increased risk for diabetes and cardiovascular disease. In this study, we investigated its prevalence among the relatives and spouses of patients with type 2 diabetes or risk factors for prediabetes, insulin resistance, and β-cell function. A total of 175 individuals were included and stratified into three groups: controls, and relatives and spouses of type 2 diabetic patients. We compared clinical characteristics consisting of a homeostatic model assessment for insulin resistance (HOMA-IR) and beta cell function (HOMA-β), a quantitative insulin sensitivity check index (QUICKI), and triglyceride glucose (TyG) index. After a multivariable linear regression analysis, the relative group was independently correlated with high fasting glucose, a high TyG index, and low β-cell function; the relatives and spouses were independently associated with a low QUICKI. The relatives and spouses equally had a higher prevalence of prediabetes. These study also indicated that the relatives had multiple factors predicting the development of diabetes mellitus, and that the spouses may share a number of common environmental factors associated with low insulin sensitivity.

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Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients

British Journal Of Nutrition ◽

10.1017/s0007114511000316 ◽

2011 ◽

Vol 106 (3) ◽

pp. 383-389 ◽

Cited By ~ 374

Author(s):

Pál Brasnyó ◽

Gergő A. Molnár ◽

Márton Mohás ◽

Lajos Markó ◽

Boglárka Laczy ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Cell Function ◽

Diabetic Patients ◽

Β Cell ◽

Type 2 Diabetic Patients ◽

Β Cell Function ◽

Type 2 Diabetic

Although resveratrol has widely been studied for its potential health benefits, little is known about its metabolic effects in humans. Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action. After an initial general examination (including blood chemistry), nineteen patients enrolled in the 4-week-long double-blind study were randomly assigned into two groups: a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo. Before and after the second and fourth weeks of the trial, insulin resistance/sensitivity, creatinine-normalised ortho-tyrosine level in urine samples (as a measure of oxidative stress), incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio in platelets were assessed and statistically analysed. After the fourth week, resveratrol significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance) and urinary ortho-tyrosine excretion, while it increased the pAkt:Akt ratio in platelets. On the other hand, it had no effect on parameters that relate to β-cell function (i.e. homeostasis model of assessment of β-cell function). The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway.

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Correlation of insulin resistance, pancreatic β-cell function and insulin sensitivity with increased Rho-associated kinase activity in PBMCs in patients with newly diagnosed type 2 diabetes

World Chinese Journal of Digestology ◽

10.11569/wcjd.v21.i12.1146 ◽

2013 ◽

Vol 21 (12) ◽

pp. 1146

Author(s):

Bin Wu

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Kinase Activity ◽

Cell Function ◽

Pancreatic Β Cell ◽

Newly Diagnosed ◽

Β Cell ◽

Β Cell Function

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Novel canine models of obese prediabetes and mild type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00466.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. E38-E48 ◽

Cited By ~ 30

Author(s):

Viorica Ionut ◽

Huiwen Liu ◽

Vahe Mooradian ◽

Ana Valeria B. Castro ◽

Morvarid Kabir ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Low Dose ◽

Cell Function ◽

High Fat ◽

Β Cell ◽

Β Cell Function

Human type 2 diabetes mellitus (T2DM) is often characterized by obesity-associated insulin resistance (IR) and β-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in β-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs ( n = 12) received a high-fat diet that increased visceral (52%, P < 0.001) and subcutaneous (130%, P < 0.001) fat and resulted in a 31% reduction in insulin sensitivity (SI) (5.8 ± 0.7 × 10−4 to 4.1 ± 0.5 × 10−4 μU·ml−1·min−1, P < 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30–15 mg/kg). The decrease in β-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose >200 mg/dl during OGTT and 77–93% AIRg reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17–74% AIRg reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased β-cell function (17–93%), and 40% lower SI. We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.

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Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.4.e659 ◽

1999 ◽

Vol 277 (4) ◽

pp. E659-E667 ◽

Cited By ~ 10

Author(s):

Karl J. Kaiyala ◽

Ronald L. Prigeon ◽

Steven E. Kahn ◽

Stephen C. Woods ◽

Daniel Porte ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Cell Function ◽

Chow Diet ◽

High Fat ◽

Β Cell ◽

Intravenous Glucose ◽

Β Cell Function ◽

Fat Feeding

The ability to increase β-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces β-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance ( K g), insulin sensitivity (SI), and the acute insulin response to glucose (AIRg) in nine dogs fed a chow diet and again after 7 wk of high-fat feeding. Additionally, we measured the effect of consuming each diet on 24-h profiles of insulin and glucose. After high-fat feeding, SI decreased by 57% ( P = 0.003) but AIRg was unchanged. This absence of β-cell compensation to insulin resistance contributed to a 41% reduction of K g( P = 0.003) and abolished the normal hyperbolic relationship between AIRg and SI observed at baseline. High-fat feeding also elicited a 44% lower 24-h insulin level ( P = 0.004) in association with an 8% reduction of glucose ( P = 0.0003). We conclude that high-fat feeding causes insulin resistance that is not compensated for by increased insulin secretion and that this contributes to the development of glucose intolerance. These effects of high-fat feeding may be especially deleterious to individuals predisposed to type 2 diabetes mellitus.

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Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Cellular Physiology and Biochemistry ◽

10.1159/000453171 ◽

2016 ◽

Vol 40 (5) ◽

pp. 1175-1185 ◽

Cited By ~ 12

Author(s):

Xiuyuan Zhang ◽

Shan Gao ◽

Jinfeng Niu ◽

Pan Li ◽

Juan Deng ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Receptor Agonist ◽

Cell Function ◽

Cb2 Receptor ◽

High Fat ◽

Β Cell ◽

Β Cell Function

Background/Aims: The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB2) receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance. Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD)/streptozotocin (STZ)-induced mice. Methods: Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist, SER601, for 2- or 4-weeks via subcutaneous implantation of osmotic minipumps. Glucose and insulin tolerance tests were performed at the end of treatment. Islets were isolated for assessment of β-cell function. Pancreases and skeletal muscles were also obtained for histological analyses. Results: Despite a lack of impact on glucose tolerance, substantial improvement on insulin sensitivity was observed in SER601-treated mice, which could partly be attributed to improved islet β-cell function, shown as increased glucose-induced insulin secretion and insulin content. No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice. However, a major decrease in body weight was recorded at the end of 4-week SER601 exposure, accompanied by a lack of epididymal adipose mass in SER601-treated mice. Conclusion: Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity. Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.

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Phenolic-enriched blueberry-leaf extract attenuates glucose homeostasis, pancreatic β-cell function, and insulin sensitivity in high-fat diet–induced diabetic mice

Nutrition Research ◽

10.1016/j.nutres.2019.09.005 ◽

2020 ◽

Vol 73 ◽

pp. 83-96 ◽

Cited By ~ 5

Author(s):

Hua Li ◽

Hye-Mi Park ◽

Hyeon-Seon Ji ◽

Jisu Han ◽

Sang-Kyum Kim ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Leaf Extract ◽

Cell Function ◽

Pancreatic Β Cell ◽

Diabetic Mice ◽

High Fat ◽

Β Cell ◽

Β Cell Function

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Impact of lack of suppression of glucagon on glucose tolerance in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.2.e283 ◽

1999 ◽

Vol 277 (2) ◽

pp. E283-E290 ◽

Cited By ~ 23

Author(s):

Pankaj Shah ◽

Ananda Basu ◽

Rita Basu ◽

Robert Rizza

Keyword(s):

Insulin Secretion ◽

Glucose Concentration ◽

Cell Function ◽

Hormone Secretion ◽

Glucose Production ◽

Glucagon Secretion ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Suppression

People with type 2 diabetes have defects in both α- and β-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a “prandial” glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic ( n = 10) or diabetic ( n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng ⋅ kg−1 ⋅ min−1, beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the “diabetic” insulin profile, lack of glucagon suppression resulted in a marked increase ( P < 0.002) in both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol ⋅ l−1 ⋅ 6 h) because of impaired ( P < 0.001) suppression of glucose production. In contrast, during the “nondiabetic” insulin profile, lack of suppression of glucagon resulted in only a slight increase ( P< 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol ⋅ l−1 ⋅ 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

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