Partners in diabetes epidemic: A global perspective

Table 1 The important physiological dysfunction negatively affect insulin synthesis and secretion

Defect	Phenomenon	Ref.
β cells failure	Insulin resistance, hyperglycaemia	Kahn[20]
↓ GLUT 4 translocation in adipocytes	↓ IRS-1 expression, ↓ PIP-3-kinase and PKB/Akt activities	Wilcox[23], Smith[24]
↑ Plasma free fatty acid	Insulin resistance, ↓ lipoprotein lipase activity, hypertriglyceridaemia	Reaven et al[26], Frayne[27]
Suppression of GLUT4 activity (muscle and liver)	Insulin dysfunction	Leroith et al[33]
Suppression of insulin receptor activity (LIRKO) (liver)	Hyperinsulinemia, hepatic and peripheral insulin resistance, glucose intolerance, insulin dysfunction	Michael et al[37]
Nuclear receptor translocator (ARNT)	↓ Insulin secretion, alterations in gene expression	Gunton et al[47], Kewley et al[48]
Suppression of IRS-2	β-cell apoptosis, insulin resistance	Rhodes[53]

ARNT: Aryl hydrocarbon nuclear receptor translocator; LIRKO: Liver-specific insulin receptor knockout; IRS: Insulin receptor substrate.

Table 2 Mitochondrial dysfunctions affecting diabetes

Defect	Consequence	Ref.
↑ Mitochondrial oxidative phosphorylation in pancreatic β-cells	↑ROS, β-cell failure	American Diabetes Association[96], Marroqui et al[98]
↓ Mitochondrial oxidative phosphorylation in skeletal muscle	↓ NADH oxidoreductase activity, ↓ citrate synthase activity, ↑ fat droplets in muscle cells, insulin resistance	Petersen et al[100], Petersen et al[101], Zhang et al[106]
↓ Size and number of mitochondria per unit	↑ Fatty acyl-CoA and diacylglycerol, ↑ protein kinase C activities, insulin resistance	Abdul-Ghani and DeFronzo[103], Lowell and Shulman[104]
↓ Expression of NRF-dependent genes	Insulin resistance	Lu et al[97], Patti et al[105]
UCP2 deficiency in β-cells	↑ Islet ATP levels, ↑ glucose-stimulated insulin secretion, obesity, β-cell failure	Zhang et al[106]

NADH: Nicotinamide adenine dinucleotide; NRF: Nuclear respiratory factor-1; ROS: Reactive oxygen species; UCP: Uncoupling protein 2.

Table 3 Lipid metabolism dysfunctions affecting on diabetes

Defect	Consequence	Ref.
Fat buildup in insulin effector cells (liver cells, muscle cells, and adipocytes)	Insulin resistance, lipotoxicity, β-cell disruption	Muoio and Newgard [112]
Adipose mitochondrial dysfunction	↑ Fatty acids levels, insulin resistance	Sparks et al[113]
Inactivated Foxa2	Lipid deposits in the liver, insulin resistance	Wolfrum et al[114]
↓ Malonyl Co-A in liver	↑ Fat oxidation, ↓ circulating free fatty acids, ↑ insulin sensitivity in both muscle and liver	An et al[115]