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

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.

Download Full-text

Non-obese patients with type 2 diabetes and prediabetic subjects: distinct phenotypes requiring special diabetes treatment and (or) prevention?

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-100 ◽

2007 ◽

Vol 32 (5) ◽

pp. 912-920 ◽

Cited By ~ 39

Author(s):

Allan Vaag ◽

Søren S. Lund

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Insulin Secretion ◽

Autoimmune Diabetes ◽

Normal Body Mass Index ◽

Obese Patients ◽

Increased Risk ◽

Obese Subjects

A major reason for the increased incidence of type 2 diabetes mellitus (T2DM) across the world is the so-called obesity epidemic, which occurs both in developed and developing countries. However, a large proportion of patients with T2DM in European and, in particular, Asian countries are non-obese. The non-obese T2DM phenotype is characterized by disproportionally reduced insulin secretion and less insulin resistance, as compared with obese patients with T2DM. Importantly, non-obese patients with T2DM have a similar increased risk of cardiovascular disease as obese T2DM patients. The risk of T2DM in non-obese patients is influenced by genetics as well as factors operating in utero indicated by low birth weight. Furthermore, this phenotype is slightly more prevalent among patients with latent autoimmune diabetes in adults, characterized by positive anti-GAD antibodies. The recently identified TCF7L2 gene polymorphism resulting in low insulin secretion influences the risk of T2DM in both obese and non-obese subjects, but is relatively more prevalent among non-obese patients with T2DM. Furthermore, the Pro12Ala polymorphism of the PPARγ gene influencing insulin action increases the risk of T2DM in non-obese subjects. Despite a “normal” body mass index, non-obese patients with T2DM are generally characterized by a higher degree of both abdominal and total fat masses (adiposity). Prevention of T2DM with lifestyle intervention is at least as effective in non-obese as in obese prediabetic subjects, and recent data suggest that metformin treatment targeting insulin resistance and non-glycemic cardiovascular disease risk factors is as beneficial in non-obese as in obese patients with T2DM. Nevertheless, non-obese patients with T2DM may progress to insulin treatment more rapidly as compared with obese patients with T2DM.

Download Full-text

The Effect of Sodium-Glucose Cotransporter 2 Inhibitor Ipragliflozin on Insulin Resistance, Hepatic Insulin Clearance, Beta-Cell Function in the Japanese Patients with type 2 Diabetes

10.21203/rs.3.rs-882630/v1 ◽

2021 ◽

Author(s):

Tsuyoshi Okura ◽

Yohei Fujioka ◽

Risa Nakamura ◽

Sonoko Kitao ◽

Yuichi Ito ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Body Composition ◽

Beta Cell Function ◽

Cell Function ◽

Insulin Clearance ◽

C Peptide ◽

Sodium Glucose Cotransporter ◽

Hepatic Insulin Clearance

Abstract Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a medication for type 2 diabetes mellitus (T2DM). Some reports showed SGLT2i improved insulin resistance, however, the effect on insulin resistance is not well established. Hepatic insulin clearance (HIC) is new pathophysiology of T2DM. The effect of SGLT2i on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i on insulin resistance, insulin secretion, incretins, body composition, and hepatic insulin clearance. Materials and Methods: We conducted a meal tolerance test (MTT), and the hyperinsulinemic-euglycemic clamp in 9 T2DM patients. 50 mg/day ipragliflozin was admitted, MTT and clamp were performed after 4 months. We calculated the postprandial C-peptide AUC to insulin AUC ratio as the HIC. We also measured GLP1, GIP, and glucagon levels during MTT. Results: Body weight, HbA1c, and body composition were not significantly changed after 4 months of treatment. Postprandial glucose, fasting, and postprandial insulin were significantly decreased. The insulin resistance of the glucose clamp was not changed, but HOMA-IR and insulin sensitivity index (ISI) were significantly improved. Incretins and glucagon were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. Fib 4 index and fatty liver index were significantly reduced. HOMA-beta and insulinogenic index was not changed but the C-peptide index was significantly increased. Conclusions: Although patients’ number was small, these results suggest that SGLT2i treatment decreased hepatic insulin resistance, increased hepatic insulin clearance, and decreased hyperinsulinemia, it might protect beta-cell function.

Download Full-text

Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

PeerJ ◽

10.7717/peerj.4542 ◽

2018 ◽

Vol 6 ◽

pp. e4542 ◽

Cited By ~ 2

Author(s):

Siyuan Kong ◽

Jinxue Ruan ◽

Kaiyi Zhang ◽

Bingjun Hu ◽

Yuzhu Cheng ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Transgenic Mice ◽

Transgenic Mouse ◽

Mouse Models ◽

Pancreatic Islet ◽

Early Stage ◽

Transgenic Mouse Models

Background Type 2 diabetes is characterized by insulin resistance accompanied by defective insulin secretion. Transgenic mouse models play an important role in medical research. However, single transgenic mouse models may not mimic the complex phenotypes of most cases of type 2 diabetes. Methods Focusing on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors, we generated single-transgenic (C/EBP homology protein, CHOP) mice (CHOP mice), dual-transgenic (human islet amyloid polypeptide, hIAPP; CHOP) mice (hIAPP-CHOP mice) and triple-transgenic (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1; hIAPP; CHOP) mice (11β-HSD1-hIAPP- CHOP mice). The latter two types of transgenic (Tg) animals were induced with high-fat high-sucrose diets (HFHSD). We analyzed the diabetes-related symptoms and histology features of the transgenic animals. Results Comparing symptoms on the spot-checked points, we determined that the triple-transgene mice were more suitable for systematic study. The results of intraperitoneal glucose tolerance tests (IPGTT) of triple-transgene animals began to change 60 days after induction (p < 0.001). After 190 days of induction, the body weights (p < 0.01) and plasma glucose of the animals in Tg were higher than those of the animals in Negative Control (Nc). After sacrificed, large amounts of lipid were found deposited in adipose (p < 0.01) and ectopically deposited in the non-adipose tissues (p < 0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of kidneys and hearts of Tg animals were significantly increased (p < 0.01). Serum C peptide (C-P) was decreased due to Tg effects, and insulin levels were increased due to the effects of the HFHSD in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone of Tg was slightly higher than those of Nc due to the effects of the 11βHSD-1 transgene and obesity. In Tg HFHSD, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the transgenic control diet (Tg ControlD) group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p < 0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice. Conclusion The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.

Download Full-text

Hepatic insulin clearance is increased in patients with high HbA1c type 2 diabetes: a preliminary report

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-001149 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001149 ◽

Cited By ~ 1

Author(s):

Tsuyoshi Okura ◽

Yohei Fujioka ◽

Risa Nakamura ◽

Mari Anno ◽

Yuichi Ito ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Gene Polymorphism ◽

Area Under The Curve ◽

Tolerance Test ◽

Insulin Clearance ◽

Model Assessment ◽

High Hba1c ◽

Hepatic Insulin Clearance

IntroductionHepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes. HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. However, hyperglycemia was suggested to enhance HIC, and it is not known whether poorly controlled diabetes increases HIC in patients with type 2 diabetes. We investigated whether HIC was increased in patients with poorly controlled diabetes, and whether HIC was associated with insulin resistance and incretins.Research design and methodsWe performed a meal tolerance test and the hyperinsulinemic–euglycemic clamp in 21 patients with type 2 diabetes. We calculated the postprandial C-peptide area under the curve (AUC)-to-insulin AUC ratio as the HIC; measured fasting and postprandial glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon levels and analyzed serum adiponectin and zinc transporter-8 (ZnT8) gene polymorphism.ResultsThe HIC significantly correlated with glycated hemoglobin (HbA1c) (r_S=0.58, p<0.01). In patients with high HIC above the median of 6.5, the mean HbA1c was significantly higher compared with low HIC below the median. Homeostatic model assessment (HOMA)-beta (r_S=−0.77, p<0.01) and HOMA-IR (r_S=−0.66, p<0.005) were correlated with HIC. The M/I value in the clamp study was correlated with HIC. GLP-1-AUC and GIP-AUC were not correlated with HIC. Glucagon-AUC was negatively correlated with HIC, but there were no significant differences between the high and low HIC groups. Adiponectin was positively correlated with HIC. The ZnT8 gene polymorphism did not affect HIC.ConclusionsThese results suggest that HIC was increased in patients with high HbA1c type 2 diabetes, low insulin secretion, low insulin resistance and high adiponectin conditions.

Download Full-text

Reduced Postprandial Hepatic Insulin Clearance via the DPP-4 Inhibitor Anagliptin Contributed to Improvement in Hyperglycemia in Patients with Type 2 Diabetes Mellitus

Diabetes ◽

10.2337/db18-1176-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1176-P

Author(s):

YASUHIRO MATSUBAYASHI ◽

TAKAHIRO ABE ◽

SAYAKA MURAGISHI ◽

AKIHIRO YOSHIDA ◽

HIDEKI SUGANAMI ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Clearance ◽

Hepatic Insulin Clearance

Download Full-text

1516-P: A Comparison of the Contributions of Impaired Insulin Secretion and Insulin Resistance to the Development of Type 2 Diabetes in a Japanese Community: The Hisayama Study

Diabetes ◽

10.2337/db19-1516-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1516-P

Author(s):

MASAHITO YOSHINARI ◽

YOICHIRO HIRAKAWA ◽

JUN HATA ◽

MAYU HIGASHIOKA ◽

TAKANORI HONDA ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Impaired Insulin Secretion ◽

Impaired Insulin

Download Full-text

Echinops Spp. Polysaccharide B Ameliorates Metabolic Abnormalities in a Rat Model of Type 2 Diabetes Mellitus

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:106-114 ◽

2020 ◽

Vol 19 (1) ◽

pp. 106-114

Author(s):

Guang Hao ◽

Xiaoyu Ma ◽

Mengru Jiang ◽

Zhenzhen Gao ◽

Ying Yang

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Insulin Receptor ◽

Skeletal Muscles ◽

Insulin Receptor Substrate ◽

Sprague Dawley

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.

Download Full-text

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

Download Full-text

Efficacy and cardiovascular safety of Thiazolidinediones

Current Drug Safety ◽

10.2174/1574886315666201026125530 ◽

2020 ◽

Vol 15 ◽

Author(s):

Raveendran Arkiath Veettil ◽

Cornelius James Fernandez ◽

Koshy Jacob

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Glucose Transporter ◽

Cell Function ◽

Cardiovascular Safety ◽

Cardiovascular Outcome Trials ◽

Glucose Transporter 2 ◽

Insulin Sensitizers

: Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though, thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.

Download Full-text