GAD positive type 2 diabetes: insulin resistance with a pronounced defect in first phase insulin secretion

This study examined the in vivo effects of Echinops spp. polysaccharide B on type 2 diabetes mellitus in Sprague-Dawley rats. We constructed a type 2 diabetes mellitus Sprague-Dawley rat models by feeding a high-fat and high-sugar diet plus intraperitoneal injection of a small dose of streptozotocin. Using this diabetic rat model, different doses of Echinops polysaccharide B were administered orally for seven weeks. Groups receiving Xiaoke pill and metformin served as positive controls. The results showed that Echinops polysaccharide B treatment normalized the weight and blood sugar levels in the type 2 diabetes mellitus rats, increased muscle and liver glycogen content, improved glucose tolerance, increased insulin secretion, and reduced glucagon and insulin resistance indices. More importantly, Echinops polysaccharide B treatment upregulated the expression of insulin receptor in the liver, skeletal muscles, and pancreas, and significantly improved the expression levels of insulin receptor substrate-2 protein in the liver and pancreas, as well as it increased insulin receptor substrate-1 expression in skeletal muscles. These two proteins play crucial roles in increasing insulin secretion and in controlling type 2 diabetes mellitus. The findings of the present study suggest that Echinops polysaccharide B could improve the status of diabetes in type 2 diabetes mellitus rats, which may be achieved by improving insulin resistance. Our study provides a new insight into the development of a natural drug for the control of type 2 diabetes mellitus.

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TYK2 Promoter Variant, a Putative Virus-Induced Diabetes Susceptibility Gene, Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

SSRN Electronic Journal ◽

10.2139/ssrn.3667638 ◽

2020 ◽

Author(s):

Hitoe Mori ◽

Hirokazu Takahashi ◽

Keiichiro Mine ◽

Ken Higashimoto ◽

Kanako Inoue ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Susceptibility Gene ◽

Diabetes Susceptibility ◽

Impaired Insulin Secretion ◽

Diabetes Susceptibility Gene ◽

Impaired Insulin ◽

Diabetes Patients

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Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

Diabetes Epidemiology and Management ◽

10.1016/j.deman.2021.100013 ◽

2021 ◽

pp. 100013

Author(s):

Froylan David Martínez-Sánchez ◽

Valerie Paola Vargas-Abonce ◽

Andrea Rocha-Haro ◽

Romina Flores-Cardenas ◽

Milagros Fernández-Barrio ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

At Risk ◽

Insulin Secretion ◽

Visceral Adiposity ◽

Visceral Adiposity Index ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

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Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22157797 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7797

Author(s):

Joseph A. M. J. L. Janssen

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Insulin Secretion ◽

Early Stage ◽

Insulin Clearance ◽

Future Research ◽

Age Related ◽

Hepatic Insulin Clearance

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

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Nateglinide increases first phase insulin secretion and enhances glucose clearance in type 2 diabetes

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(00)81689-7 ◽

2000 ◽

Vol 50 ◽

pp. 69

Author(s):

StevenE. Kahn ◽

Brenda Montgomery ◽

Monica Ligueros-Saylan ◽

Chyi-Hung Hsu ◽

Damayanthi Devineni ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Clearance ◽

First Phase Insulin Secretion

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Overnight inhibition of insulin secretion restores pulsatility and proinsulin/insulin ratio in type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.3.e520 ◽

2000 ◽

Vol 279 (3) ◽

pp. E520-E528 ◽

Cited By ~ 71

Author(s):

Thomas Laedtke ◽

Lise Kjems ◽

Niels Pørksen ◽

Ole Schmitz ◽

Johannes Veldhuis ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Plasma Glucose ◽

Glucose Concentration ◽

Plasma Glucose Concentration ◽

Molar Ratio ◽

Β Cell ◽

First Phase Insulin Secretion ◽

Clinical Experiments

Impaired insulin secretion in type 2 diabetes is characterized by decreased first-phase insulin secretion, an increased proinsulin-to-insulin molar ratio in plasma, abnormal pulsatile insulin release, and heightened disorderliness of insulin concentration profiles. In the present study, we tested the hypothesis that these abnormalities are at least partly reversed by a period of overnight suspension of β-cell secretory activity achieved by somatostatin infusion. Eleven patients with type 2 diabetes were studied twice after a randomly ordered overnight infusion of either somatostatin or saline with the plasma glucose concentration clamped at ∼8 mmol/l. Controls were studied twice after overnight saline infusions and then at a plasma glucose concentration of either 4 or 8 mmol/l. We report that in patients with type 2 diabetes, 1) as in nondiabetic humans, insulin is secreted in discrete insulin secretory bursts; 2) the frequency of pulsatile insulin secretion is normal; 3) the insulin pulse mass is diminished, leading to decreased insulin secretion, but this defect can be overcome acutely by β-cell rest with somatostatin; 4) the reported loss of orderliness of insulin secretion, attenuated first-phase insulin secretion, and elevated proinsulin-to-insulin molar ratio also respond favorably to overnight inhibition by somatostatin. The results of these clinical experiments suggest the conclusion that multiple parameters of abnormal insulin secretion in patients with type 2 diabetes mechanistically reflect cellular depletion of immediately secretable insulin that can be overcome by β-cell rest.

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Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00430.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1694-E1701 ◽

Cited By ~ 17

Author(s):

Jane J. Kim ◽

Yoshiaki Kido ◽

Philipp E. Scherer ◽

Morris F. White ◽

Domenico Accili

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Cell Response ◽

Cell Mass ◽

Comprehensive Treatment ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

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Type2Diabetes—Effect of Compensatory Oversecretion as a Reason forβ-Cell Collapse

International Journal of Experimental Diabetes Research ◽

10.1080/15604280214276 ◽

2002 ◽

Vol 3 (3) ◽

pp. 153-158 ◽

Cited By ~ 7

Author(s):

Valdemar Grill ◽

Anneli Björklund

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Clinical Studies ◽

Structural Damage ◽

Therapeutic Potential ◽

Cell Collapse

Insulin secretion declines progressively before and during the course of type 2 diabetes. Evidence indicates that this process is, in part, secondary to increased requirement for insulin secretion that is brought about by insulin resistance and by hyperglycemia. The effects of over-secretion extend far beyond a mere reduction of available insulin stores and may cause not only functional but also structural damage. The time is ripe for clinical studies, which explore the therapeutic potential of reducing over-secretion.

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Decreased Plasma Maresin 1 Concentration Is Associated with Diabetic Foot Ulcer

Mediators of Inflammation ◽

10.1155/2020/4539035 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Tian Miao ◽

Bangliang Huang ◽

Niexia He ◽

Lihua Sun ◽

Guangsheng Du ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Diabetic Foot ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Model Assessment ◽

Homeostasis Model Assessment

Aims. To assess the maresin 1 (MaR1) contents in type 2 diabetic patients with or without diabetic foot ulcer and to analyze the association of MaR1 concentrations with several metabolism-related parameters. Methods. Plasma MaR1 concentrations were analyzed in 96 subjects with normal glucose tolerant (NC, n=43), type 2 diabetes (T2DM, n=40), or diabetic foot ulcer (DFU, n=13). The intravenous glucose tolerance test (IVGTT) and biochemical parameters were measured in all participants. Results. Plasma MaR1 concentrations were significant decreased in type 2 diabetes patient with or without DFU compared with NC (both P<0.001) and were lowest in DFU patients among these 3 groups. (DFU vs. T2DM, P<0.05). Plasma MaR1 concentrations were negatively correlated with BMI, waist circumference (Wc), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-c, FPG, 2hPG, HbA1c, and homeostasis model assessment for insulin resistance (HOMA-IR) (all P<0.05) and were positively correlated with HDL-c, acute insulin response (AIR), area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and homeostasis model assessment for beta-cell function (HOMA-β) (all P<0.05). After adjusting for age and sex, Wc, WHR, TG, FPG, 2hPG, HbA1c, HOMA-IR, AIR, AUC, and HOMA-β remain statistically significant (all P<0.05). Conclusions. Plasma MaR1 concentration were decreased in T2DM with or without DFUs and were the lowest in DFU patients. The decreased plasma MaR1 strongly associated with obesity, impaired glucose and lipid metabolism, reduced first-phase of glucose-stimulated insulin secretion, and enhanced insulin resistance.

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