Abstract

Surging pandemicity of T2DM: The time-old and conventional wisdom holds that T2DM is a metabolic disease characterized by hyperglycemia due to a deficient action of insulin and that diabetic complications result due to high circulating glucose levels and glycation products. But, the characterization of T2DM with hyperglycemia is an overt simplification. T2DM is rather a complex interplay of metabolic alterations herald by hyperglycemia and it may be interesting to explore the complexities encompassing etiology, pathophysiology and genesis of T2DM and its complications.

Altered insulin homeostasis: In due course, in pre-diabetes and later in T2DM, the tissues develop resistance to the metabolic actions of insulin, culminating as decreased insulin action and hyperglycemia resulting from various factors. The IR is inherently variable and occurs at variable period in different body tissues, the major contributors to IR being obesity and physical inactivity.

The compexities of T2DM: The altered insulin signaling may be an important factor in the genesis of diabetic complications. The insulin sensitivity regulates β-cell function, and when glucose and lipids are increased for a long period, the β-cells function is compromised. The IR may seem to be deleterious in general, as it is associated with MetS, T2DM and allied metabolic disorders, but has certain protective and beneficial role. The pentosephosphate pathway is impaired due to thiamine deficiency and correction of thiamine deficiency by thiamine, restores IR and biochemical dysfunctions. Aging is the irreversible contributor to metabolic decline and related disorders, including T2DM. EDCs pose threats to metabolic homeostasis, being the paradox and a product of technological developments.

Conclusion-metabolic response and adaptations: The intensive treatment of T2DM with insulin may be harmful in obese patients who are unable to improve lifestyle to achieve a negative energy balance. The insulin-responsive tissues, such as the heart, skeletal muscle, adipose tissue, and the liver, are able to protect themselves from nutrient-induced damage by developing IR. Other tissues, such as nerves, eye, kidney and the vasculature, are less protected by IR. Here, the hypotheses relating to ‘IR as adaptive defence mechanism’ and ‘insulin-induced metabolic stress’ are attractive concepts and need to be explored further, in light of current research and new studies available.

Keywords: Metabolic syndrome; Type 2 diabetes mellitus; Insulin resistance; Insulin homeostasis; Thiamine deficiency; Endocrine disrupters; Gender related adiposity; Metabolic stress

Abbreviations: BMI: Body Mass Index; BPA: Bisphenol A; CVD: Cardio Vascular Disease; CNS: Central Nervous System; CoA: Coenzyme A; DPP-4: Dipeptidyl peptidase-4; DM: Diabetes Mellitus; T2DM: Type 2 Diabetes Mellitus; EDCs: Endocrine Disrupting Chemicals; ER: Endoplasmic Reticulum; GLUT: Glucose Transporter; DDT: Dichlorodiphenyltrichloroethane; FFA: Free Fatty Acids; GLP-1: Glucagon Like Peptide-1; POPs: Persistent Organic Pollutants; GDPH: Glyceraldehyde 3-Phos-Phate Dehydrogenase; GISS: Glucose Stimulated Insulin Secretion; NPY/AgRP: Neuropeptide Y/Agouti Related Peptide; IR: Insulin Resistance; SGLT2: Sodium-Glucose-Cotrans-Porter-2; MAPK: Mitogen-Activated Protein Kinase; GH: Growth Hormone; IGF: Insulin like Growth Factor; MetS: Metabolic Syndrome; NEFA: Non-Esterified Fatty Acids; NPY-Y1: Neuropeptide Y1 Receptor Y1; OHA: Oral Hypoglycaemic Agent; PVD: Peripheral Vascular Disease; POMC: Pro-Opiomelanocortin; PVN: Paraventricular Nucleus; PKC: Protein kinase C; PBDE: Poly Brominated Diphenyl Ether; TZDs: Thiazolidinediones; PCBs: Polychlorinated Biphenyl Ethers; PI3K/PKBAKT: Phosphoinositide-3-Kin-Ase/ Protein Kinase B (or) AKT; T1DM: Type 1 Diabetes Mellitus