Insulin resistance can be inherited or acquired. Obesity, aging, physical inactivity, overeating, and accumulation of nonestrified (free) fatty acids (NEFAs) are known causes of insulin resistance. Normally, cytoplasmic NEFAs in the form of long-chain fatty acyl coenzyme A (LCFA-CoA) are transported into mitochondria for β-oxidation, a process that is gated by carnitine palmitoyl transferase (CPT)-1 and CPT-2 (the shuttle enzymes located in the outer and inner mitochdrial membrane; Figure 1.4). This shuttle process ensures that NEFAs do not accumulate excessively in the cytoplasm. Inhibition of that process leads to the accumulation of LCFA-CoA, which can lead to lipotoxicity.13 Also, intracellular accumulation of fatty acids can activate protein kinase C (PKC) via diacylglycerol (DAG), leading to aberrant phosphorylation at serine or threonine residues instead of tyrosine (Figure 1.4). As noted, serine or threonine phosphorylation produces insulin resistance by short-circuiting the normal insulin signal transduction that leads to GLUT4 translocation and glucose transport into cells. Interestingly, acetyl CoA, a product of glycolysis in the Krebs cycle, can be converted to malonyl CoA by the enzyme acetyl CoA carboxylase (ACC). Malonyl CoA is a potent inhibitor of CPT-1, a process that thwarts mitochondrial fat oxidation and promotes the accumulation of fatty acids in the cytosol.36 Glucose abundance also increases the formation of intracellular DAG. Thus, multiple metabolic pathways link intracellular glucose abundance (usually derived from carbohydrate consumption) to impaired fat oxidation, cytosolic fat accumulation, risk of lipotoxicity, and insulin resistance (Figure 1.4). Caloric restriction through the reduction of carbohydrate and fat intake has been shown to improve insulin sensitivity and prevent T2D.37,38
Figure 1.4—Schema showing insulin signaling and interactions with glucose (G) and fatty acid metablism.
Increased Lipolysis
As a consequence of insulin resistance in adipocytes, the inhibitory effects of insulin on plasma NEFA levels and adipocyte NEFA turnover are markedly impaired.13,39,40 The net effect is increased lipolysis and NEFA turnover in the setting of insulin resistance. Thus, patients with T2D are exposed to chronic elevation in plasma NEFA levels, which leads to increased gluconeogenesis, exacerbation of insulin resistance in hepatocytes and myocytes, and impairment of insulin secretion.41,42 Furthermore, a morphological shift to a larger adipocyte size occurs in the setting of insulin resistance along with aberrant adipocyte function, resulting in the increased secretion of proinflammatory molecules and decreased production of adiponectin, a protective adipocytokine. Notably, the enlarged adipocytes in insulin-resistant subjects have a reduced capacity for storing fat, which causes excessive lipid deposition at ectopic sites, such as muscle, liver, β-cells, and vascular smooth cells.13,43 As noted, the intracellular accumulation of fatty acids leads to lipotoxicity, with dire consequences for cellular function, insulin sensitivity, and insulin secretion.13
Insulin Secretion
Under normal conditions, the pancreatic β-cells secrete insulin in response to glucose stimulation through a series of transmembrane electrical reactions. Glucose metabolism in β-cells generates bursts of action potentials that ultimately lead to calcium influx. The adenosine triphosphate (ATP)–sensitive potassium channel (KATP) normally maintains the β-cell resting membrane potential, thereby preventing calcium entry. The KATP channel is closed when the ratio of ATP to adenosine diphosphate rises within the β-cells as occurs during glucose metabolism. The resultant depolarization (change in electrical charge) of the β-cell membrane drives calcium into the cell, which then triggers insulin secretion (Figure 1.5). Agents that open the KATP channel (e.g., diazoxide) reverse the depolarization and inhibit insulin secretion by the β-cells. The β-cell mass is reduced in T2D patients because of apoptosis induced by toxic islet amyloid, oxidative stress, inflammatory cytokines, and other mechanisms.44–46
Figure 1.5—Process of glucose-stimulated insulin secretion by the pancreatic β-cell.
Hepatic Glucose Production
In the prospective study of Pima Indians, HGP remained normal during the transition from normal glucose tolerance to IGT, but increased by 15% with further progression to T2D.14 In patients with established T2D, the rate of hepatic gluconeogenesis is not suppressed postprandially (as occurs normally). Thus, the upregulated HGP becomes a key determinant of fasting as well as postprandial glucose excursions in T2D. The increased HGP is triggered by an increased flux of lipolytic products and other glucose precursors and is exacerbated by hepatic insulin resistance.
Glucagon and Incretins
Glucagon hypersecretion by the pancreatic α-cells is a characteristic of both T1D and T2D.47 The hyperglucagonemia in patients with diabetes is particularly inappropriate in the postprandial period when glucon levels are expected to be suppressed. The failure of postprandial glucagon suppression in patients with T1D and T2D results from loss of pulsatile intraislet insulin secretion and leads to exaggerated postprandial glucose excursions.48 Autopsy studies in patients with T2D further show preservation of α-cell mass, despite marked depletion of β-cell mass.44 Incretin hormones (glucagon-like peptide [GLP]-1 and glucose-dependent insulinotropic peptide [GIP]), normally secreted by the enterocytes in response to food, amplify postprandial insulin secretion and suppress glucagon secretion. Emerging data indicate that T2D is associated with impaired incretin secretion and relative resistance to the action of incretin hormones. The major pathophysiological defects in T2D are summarized in Figure 1.6.13
Figure 1.6—Major pathophysiological defects in type 2 diabetes.
Renal Glucose Reabsorption
Under normal conditions, ~180 g of glucose are filtered by the glomerulus, but no glycosuria ensues because of efficient reabsorption by renal tubules. Renal tubular glucose reabsorption is mediated by specialized adluminal sodium glucose cotransporters (SGLT)-1 and SGLT2 (the latter being the major transporter) and basolateral glucose transporters GLUT1 and GLUT2 molecules. In patients with diabetes, hyperglycemia exceeds renal tubular maximum, leading to glycosuria commensurate with the degree of hyperglycemia. Mutations in the SGLT2 gene have been described in patients with familial renal glycosuria, a benign condition that is not associated with diabetes or hyperglycemia.49 It appears that renal glucose reabsorption may be inappropriately efficient in the setting of hyperglycemia and that SGLT2, GLUT1, and GLUT2 may be upregulated in the kidney of patients with T2D.13,50,51 Indeed, several SGLT2 inhibitors have now been approved for the treatment of T2D and are effective in decreasing hyperglycemia by promoting renal glucose excretion.
Central Dopaminergic Pathways
Emerging data indicate that central nervous system dopaminergic pathways modulate food intake, and glucose, energy, and weight homeostasis. Decreased dopaminergic tone and polymorphisms of the dopamine D2 receptor are associated with increased risks of obesity and T2D.52,53 Conversely, augmentation of dopaminergic activity has been shown to improve glucose tolerance and insulin sensitivity, reduce adiposity, and improve lipid profile.54,55 A quick-release form of bromocriptine (BQR) has been approved for the treatment of T2D on the basis of its ability to “reset” central dopaminergic tone and improve related neurotransmission pathways.56 An ancillary mechanism of action of BQR may be its ability to reduce adrenergic tone, thus mitigating adrenergic-related increase in insulin resistance, glucose, and blood pressure.56,57
Conclusion
Current understanding indicates that multiple pathophysiological defects underlie