Molecular Basis of Pathogenesis of Diabetes Mellitus Type 2- a New Perspective

Decreased insulin secretion due to beta cell dysfunction of the pancreas and defective utilization of insulin due to insulin resistance / Hyperinsulinemia are two important issues in the pathogenesis of DM2. There are many explanations in the literature to account for these two observed phenomena and their interrelationship. DM2 is believed to occur due to a complex interplay of environmental andBehavioural factors in genetically predisposed persons. Among the prominent theories explaining the pathogenesis of DM2, the viscera- Portal hypothesis, the Ectopic fat hypothesis and the adipose tissue as an endocrinal gland are prominent. Besides, the role played by oxidative stress, metabolic stress, mitochondrial dysfunction, endoplasmic reticulum stress, etc. are also advanced. It is felt that basic to and at the core of all the observed facts, is the shift of energy metabolism from normal glycolysis to B- oxidation of fats. Hence, how B - oxidation prevails over glycolysis is the fundamental issue to be addressed together with its interrelationships with insulin resistance, as to which is the cause and which is the effect. At the molecular level, an attempt to find answers to the above questions is made in this paper.To this extent, the Randle fatty acid cycle (Substrate competition theory of Randle) is suitably modified and applied to explain the switch of Energy metabolisms in DM2 .Defective disulfide bond formation of the insulin receptor which makes it physiologically ineffective, is suggested as the cause of the insulin resistance where as the prevailing molecular mechanisms stress on post-receptor signaling defect. The cause and effect of both are discussed. This line is considered to be a departure from traditional approaches broached above and briefly outlined in this article.

Relationship between hyperglycemia and pancreatic beta cell dysfunction in critically ill children / 中国小儿急救医学

Objective To analyse the relationship between insulin resistance and the pancreatic beta cell dysfunction in critically ill children with hyperglycemia,to investigate the relationship between the pancreas injury and pancreatic beta cells dysfunction.Methods Seven hundred and thirty-six critically ill children admitted in PICU of Hunan Children's Hospital from Nov 2012 to Mar 2013 were reviewed and analyzed.According to the maximum intravenous blood glucose within 24 h after admission,they were divided into severely elevated group (blood glucose ≥11.1 mmol/L,n =67),slightly elevated group(blood glucose 6.1 ～ 11.1 mmol/L,n =361) and control group (blood glucose ≤ 6.1 mmo/L,n =308).Serum insulin,C peptide,serum amylase,lipase,urinary amylase,HOMA-β,HOMA-IR were compared among 3 groups.According to the severity of sepsis,they were divided into non-sepsis group (n =414),sepsis group (n =237),severe sepsis group (n =64),septic shock group (n =21).Blood glucose,serum insulin,C peptide,HOMA-βand HOMA-IR were compared among 4 groups.Results (l)The levels of insulin,C peptide,blood amylase,lipase and urine amylase were gradually increased with elevated blood sugar(rs =0.235,P ＜ 0.05;C =0.142,P ＜ 0.05 ; rs =0.142,P ＜ 0.05 ; rs =0.119,P ＜ 0.05 ; r.s =0.093,P ＜ 0.05).The differences among 3 groups were significant (P ＜ 0.05).The levels of serum amylase (IU/L) [102.81 (10.48-191.69)],lipase(U/L) [69.75(10.67-121.85)] were higher than upper limit of normal in severely elevated group.HOMA-β fell to 18.75％ in severely elevated group.The level of HOMA-β was decreased with the increase of blood sugar level (rs =-0.108,P ＜ 0.05).The level of HOMA-IR was increased with the elevated blood sugar level(rs =0.455,P ＜ 0.05).(2) The levels of blood glucose,insulin,C peptide and HOMA-β were significantly different among 4 groups of non-sepsis,sepsis,severe sepsis and septic shock group (P ＜ 0.05),HOMA-IR showed no significant difference among 4 groups (P ＞ 0.05).The levels of blood sugar increased to 9.21 (6.21-19.60) mmol/L,HOMA-β declined to 10.52％ in septic shock group,and blood glucose,insulin,C peptide,HOMA-β were significantly different compared with the other 3 groups (P ＜ 0.05).Conclusion Hyperglycemia is associated with insulin resistance and pancreatic β cells dysfunction in critically ill children,the cause of beta cell dysfunction is secondary to pancremic injury.Pancreatic beta cells dysfunction inducing hyperglycemia is more significant than insulin resistance in sepsis children.

Glucolipotoxicity in Pancreatic beta-Cells

The recent epidemic of type 2 diabetes in Asia differs from that reported in other regions of the world in several key areas: it has evolved over a much shorter time, in an earlier stage of life, and in people with lower body mass indices. These phenotypic characteristics of patients strongly suggest that insulin secretory defects may perform a more important function in the development and progression of diabetes. A genetic element clearly underlies beta-cell dysfunction and insufficient beta-cell mass; however, a number of modifiable factors are also linked to beta-cell deterioration, most notably chronic hyperglycemia and elevated free fatty acid (FFA) levels. Neither glucose nor FFAs alone cause clinically meaningful beta-cell toxicity, especially in patients with normal or impaired glucose tolerance. Thus the term "glucolipotoxicity" is perhaps more appropriate in describing the phenomenon. Several mechanisms have been proposed to explain glucolipotoxicity-induced beta-cell dysfunction and death, but its major factors appear to be depression of key transcription factor gene expression by altered intracellular energy metabolism and oxidative stress. Therefore, stabilization of metabolic changes induced by glucolipotoxicity in beta-cells represents a new avenue for the treatment of type 2 diabetes mellitus.

Genetics of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance diagnosed for the first time during pregnancy. The pathogenesis of GDM is characterized by relatively reduced insulin secretion insufficient to meet the increased insulin demand, which is quite similar to that of type 2 diabetes mellitus. Thus GDM is considered to have a common genetic background as type 2 diabetes mellitus. However, only limited information is available for the genetic basis of GDM. In this review article, we will briefly discuss the definition, epidemiologic features, and pathophysiology of GDM. In addition, we will present the data of two recent genetic association studies regarding GDM. Most of the previously proven type 2 diabetes associated with single nucleotide polymorphisms were also associated with the risk of GDM. Rapidly increasing knowledge in genetics of GDM will generate new insights into the pathophysiology, treatment, and prevention of GDM.

Genetics of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance diagnosed for the first time during pregnancy. The pathogenesis of GDM is characterized by relatively reduced insulin secretion insufficient to meet the increased insulin demand, which is quite similar to that of type 2 diabetes mellitus. Thus GDM is considered to have a common genetic background as type 2 diabetes mellitus. However, only limited information is available for the genetic basis of GDM. In this review article, we will briefly discuss the definition, epidemiologic features, and pathophysiology of GDM. In addition, we will present the data of two recent genetic association studies regarding GDM. Most of the previously proven type 2 diabetes associated with single nucleotide polymorphisms were also associated with the risk of GDM. Rapidly increasing knowledge in genetics of GDM will generate new insights into the pathophysiology, treatment, and prevention of GDM.

Disfunción beta pancreática

La disfunción beta pancreática es una realidad fisiopatológica que conduce a una pérdida gradual en la eficacia de los opciones terapéuticas utilizadas en la DM. La evidencia actual establece que tanto en los diabéticos como en la condición de prediabetes, la disfunción de la célula beta es el primer defecto demostrable con limitación de la capacidad de compensación en presencia de resistencia a la insulina. Cada vez toma más importancia la necesidad de mantener el control glucémico a largo plazo utilizando opciones terapéuticas que aseguren la preservación del funcionamiento de la masa beta pancreática.

The dysfunction pancreatic beta is a physiopatological reality that conducts to a gradual loss in the efficacy of the therapeutic options utilized in the DM. The current evidence establishes that so much in the diabetic as in the condition of prediabetes, the dysfunction of the cell beta is the first demonstrable defect with limitation of the capacity of clearing in the presence of resistance to the insulin. Each time takes more importance the need to maintain the control glucémico long-term utilizing therapeutic options that assure the preservation of the operation of the pancreatic mass.

Glucose Toxicity and Pancreatic Beta Cell Dysfunction in Type 2 Diabetes / 당뇨병

The adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations (i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species (ROS) that can impair insulin gene expression and beta cell function. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause beta cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. The intracellular peroxide levels of the pancreatic islets (INS-1 cells, rat islets) by flow cytometry were increased in the high glucose media compared to 5.6 mM glucose media. The insulin, MafA, PDX-1 mRNA levels and glucose stimulated insulin secretion (GSIS) were decreased in high glucose media compared to 5.6 mM glucose media. The HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions. Also, we observed decreased glutathione level, gamma-GCS expression and increased oxidized LDL, malondialdehyde level at leukocytes and mesothelial cells from patients with Korean Type 2 Diabetes (esp, poorly controlled patients). In conclusion, this pathophysiologic sequence sets the scene for considering antioxidant therapy as an adjunct in the management of diabetes, especially type 2 Diabetes.

Liver Cirrhosis and Diabetes Mellitus / 대한간학회지

No abstract available.

Serum insulin, proinsulin, and proinsulin/insulin ratio in type 2 diabetic patients / 대한내과학회지

BACKGROUND: Although insulin resistance and decreased insulin secretion are characteristics of establised type 2 DM, which of these metabolic abnormalities is the primary determinant of type 2 DM is controversial. It is also not well known how insulin resistance and beta cell dysfunction influence serum insulin, proinsulin, proinsulin/insulin ratio in type 2 DM. METHODS: We compared serum insulin, proinsulin, proinsulin/insulin ratio in type 2 diabetic patients and control subjects. We investigated the relationship between serum insulin, proinsulin, proinsuolin/insulin ratio and several biochemical markers which represent insulin resistance or beta cell function. RESULTS: Proinsulin, total insulin, and proinsulin/insulin ratio were significantly higher in type 2 DM than control(p< 0.001). In diabetic patients, proinsulin was correlated with fasting c-peptide(r=0.43, p=0.002), postprandial 2 hour blood glucose(r=0.213, p=0.05), and triglyceride(r=0.28, p=0.022). Total insulin was correlated with urinary albumin excretion rates(r=0.224, p=0.025) and body mass index(r=0.269, p=0.014). Proinsulin/insulin ratio was positively correlated with fasting c-peptide(r=0.236, p=0.031), fasting blood glucose(r=0.264, p=0.015), postprandial 2 hour blood glucose(r=0.277, p=0.001), and triglyceride(r=0.428, p< 0.001). In control subjects, fasting insulin was correlated with triglyceride (r=0.366, p=0.002). Proinsulin/insulin ratio was correlated with age(r=0.241, p=0.044). CONCLUSION: The serum levels of insulin and proinsulin seems to be associated with several markers of insluin resistance. The proinsulin/insulin ratio might represent beta cell function rather than insulin resistance. But more studies are needed to clarify the mechanism of elevated proinsulin/insulin ratio in type 2 DM.

Serum Insulin, Proinsulin and Proinsulin/Insulin Ratio in Type 2 Diabetic Patients: As an Index of beta-Cell Function or Insulin Resistance

BACKGROUND: Although insulin resistance and decreased insulin secretion are characteristics of established type 2 DM, which of these metabolic abnormalities is the primary determinant of type 2 DM is controversial. It is also not well known how insulin resistance and beta cell dysfunction influence serum insulin, proinsulin, proinsulin/insulin ratio in type 2 DM. METHODS: We compared serum insulin, proinsulin and proinsulin/insulin ratio in type 2 diabetic patients and control subjects. We also investigated the relationship between serum insulin, proinsulin and proinsulin/insulin ratio and several biochemical markers which represent insulin resistance or beta cell function. RESULTS: Insulin, proinsulin and proinsulin/insulin ratio were significantly higher in type 2 DM than control(p < 0.001). In diabetic patients, total insulin level was correlated with urinary albumin excretion rates(r = 0.224, p = 0.025) and body mass index(r = 0.269, p = 0.014). Proinsulin level was correlated with fasting C-peptide(r = 0.43, p = 0.002), postprandial 2 hour blood glucose(r = 0.213, p = 0.05) and triglyceride(r = 0.28, p = 0.022). Proinsulin/insulin ratio was positively correlated with fasting C-peptide(r = 0.236, p = 0.031), fasting blood glucose (r = 0.264, p = 0.015), postprandial 2 hour blood glucose(r = 0.277, p = 0.001) and triglyceride(r = 0.428, p < 0.001). In control subjects, insulin level was correlated with triglyceride(r = 0.366, p = 0.002). Proinsulin/insulin ratio was correlated with age(r = 0.241, p = 0.044). CONCLUSION: The serum levels of insulin and proinsulin seem to be associated with several markers of insulin resistance. Whereas proinsulin/insulin ratio might represent beta cell function rather than insulin resistance. But more studies are needed to clarify the mechanisms of elevated proinsulin/insulin ratio in type 2 DM.