In summary, postbinding defects in insulin action primarily are responsible for the insulin resistance in T2DM. Diminished insulin binding, when present, is modest and secondary to downregulation of the insulin receptor by chronic hyperinsulinemia. In type 2 diabetic patients with overt fasting hyperglycemia, a number of postbinding defects have been demonstrated, including reduced insulin receptor tyrosine kinase activity, insulin signal transduction abnormalities, decreased glucose transport, diminished glucose phosphorylation, and impaired glycogen synthase activity. The glycolytic/glucose oxidative pathway is largely intact and, when defects are observed, they appear to be acquired secondary to enhanced FFA/lipid oxidation. From the quantitative standpoint, impaired glycogen synthesis represents the major pathway responsible for the insulin resistance in T2DM, and is present long before the onset of overt diabetes, that is, in normal glucose-tolerant, insulin-resistant prediabetic subjects and in individuals with IGT. The impairment in glycogen synthase activation appears to result from a defect in the ability of insulin to phosphorylate IRS-1, causing a reduced association of the p85 subunit of PI-3 kinase with IRS-1 and decreased activation of the enzyme PI-3 kinase.
The adipocyte, FFA metabolism, and lipotoxicity
Considerable evidence implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in T2DM [1–3,39,110,197,311–314]: (i) fat cells are resistant to insulin’s antilipolytic effect, leading to day-long elevation in the plasma FFA concentration [1–3,39,110,208,311–315]; (ii) chronically increased plasma FFA levels stimulate gluconeogenesis [316–318], induce hepatic/muscle insulin resistance [319–321], and impair insulin secretion [110,322]. These FFA-induced disturbances are referred to as lipotoxicity; (iii) dysfunctional fat cells produce excessive amounts of insulin resistance–inducing, inflammatory, and atherosclerotic-provoking adipocytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines such as adiponectin [311,312]; (iv) enlarged fat cells are insulin resistant and have diminished capacity to store fat [323,324]. When adipocyte storage capacity is exceeded, lipid “overflows” into muscle, liver, and β cells, causing muscle/hepatic insulin resistance and impaired insulin secretion (reviewed in  and ). This represents another form of lipotoxicity. Lipid can also overflow into arterial vascular smooth cells, leading to the acceleration of atherosclerosis.
Using 14C-palmitate in combination with the insulin clamp technique , the antilipolytic effect of insulin has been shown to be markedly impaired in lean type 2 diabetic subjects, as well as in obese nondiabetic subjects . In both type 2 diabetic (Figure 25.13) and obese nondiabetic subjects, the ability of insulin to suppress the plasma FFA concentration and inhibit FFA turnover is impaired compared with lean normal glucose-tolerant subjects at all plasma insulin-concentrations spanning the physiologic and pharmacologic range.
Many investigators [317,318,321,325] have demonstrated that a physiologic elevation in the plasma FFA concentration stimulates HGP and impairs insulin-stimulated glucose uptake in liver  and muscle [318–321,325–330]. Chronically elevated plasma FFA levels also inhibit insulin secretion [110,322], especially in genetically prone individuals.
According to the Randle [310,331] cycle of substrate competition, elevated FFA oxidation in muscle reciprocally impairs glucose oxidation. Although clearly there is substrate competition between FFA and glucose with respect to oxidative metabolism [323,333], FFAs have been shown to have independent effects to inhibit glycogen synthase [334,335] and both glucose transport and glucose phosphorylation [328,336].
Further, physiologic elevation in the plasma FFA concentration for as little as 4 hours markedly impairs insulin signal transduction and inhibits insulin-mediated glucose disposal by 30–35% in healthy lean normal glucose-tolerant subjects . The elevation in plasma FFA concentration caused a dose-response inhibition of muscle insulin receptor tyrosine phosphorylation, IRS-1 tyrosine phosphorylation, PI-3 kinase activity, and Akt serine phosphorylation (Figure 25.14). Conversely, reduction in the plasma FFA concentration with acipimox in T2DM individuals enhances insulin sensitivity by ∼30% in association with an increase in insulin signaling, glycogen synthesis, and glucose oxidation [338,339].
After fatty acids enter the cell, they can be converted to triglycerides, which are inert, or to toxic lipid metabolites such as fatty acyl CoAs, diacylglycerol, and ceramide . Using magnetic resonance spectroscopy, the intramyocellular triglyceride content has been shown to be increased in type 2 diabetic subjects [338,340]. Fatty acyl CoAs, which are known to inhibit insulin signaling [341,342], are also significantly increased in muscle in diabetic subjects [338,343].
Peroxisome proliferator-activated γ coactivator-1 (PGC-1) is the master regulator of mitochondrial biogenesis  and augments the expression of multiple genes involved in mitochondrial oxidative phosphorylation [345–347]. In individuals with T2DM and in the normal glucose-tolerant, insulin-resistant offspring of two diabetic parents the expression of PGC-1, nuclear receptor factor-1, and multiple other genes involved in oxidative phosphorylation are markedly reduced in muscle and are strongly correlated with the defect in glucose oxidation and whole body (muscle) insulin resistance [211,343,348]. The reduced expression and activity of these key mitochondrial genes in the NGT offspring strongly suggests a genetic etiology for the mitochondrial dysfunction. However, there also is evidence that the mitochondrial defect is acquired, at least in part [349–351]. Treatment of diabetic patients with pioglitazone markedly improves insulin sensitivity in association with a reduction in intramyocellular lipid and fatty acylCoA concentrations. The decrement in muscle fatty acyl CoA content is closely related to the improvement in insulin-stimulated muscle glucose disposal [340,343]. Reduced intramyocellular fatty acyl CoA content with acipimox, a potent inhibitor of lipolysis, caused a similar improvement in insulin-mediated glucose disposal [338,339]. Increased intramyocellular levels of diacylglycerol [330,352] and ceramides [353,354] have been demonstrated in type 2 diabetic and obese nondiabetic subjects and shown to be related to the insulin resistance and impaired insulin signaling in muscle. A 48-h lipid infusion, designed to increase the plasma FFA concentration ∼1.5- to twofold, inhibits the expression of PGC1α, PGC1β, PDHA1, and multiple mitochondrial genes involved in oxidative phosphorylation in muscle , thus mimicking the pattern of gene expression observed in type 2 diabetic subjects and in the normal glucose-tolerant, insulin-resistant offspring of two type 2 diabetic parents [355,356]. Further, in mitochondria isolated from muscle of normal glucose-tolerant subjects  physiologic palmitoyl carnitine concentrations (>4 μmol L−1) caused a marked inhibition of ATP synthesis and a decrease in the inner mitochondrial membrane potential, which provides the electromotive driving force for electron transport. Collectively, these findings provide strong support for lipotoxicity and adipocyte insulin resistance in the pathogenesis of T2DM.
Alpha cell and glucagon
It long has been known that the basal plasma glucagon concentration is elevated in type 2 diabetic individuals [184–186, 357,358]. The important contribution of elevated fasting plasma glucagon levels to the increased basal rate of HGP in type 2 diabetic individuals was provided by Baron et al. . Compared with control subjects, diabetic individuals had a markedly elevated rate of basal HGP, which correlated closely with the increase in fasting plasma glucagon concentration. Somatostatin infusion reduced the plasma glucagon concentration by 44% in association with a 58% decrease in basal HGP (Figure 25.15). These results conclusively demonstrate the pivotal role of hyperglucagonemia in the pathogenesis of fasting hyperglycemia in T2DM.There also is evidence that the liver is hypersensitive to the stimulatory effect of glucagon in hepatic gluconeogenesis .
In normal glucose-tolerant subjects, plasma glucagon levels decline following a meal and the decrease in portal vein glucagon concentration contributes to the suppression of HGP . In contrast, following ingestion of a mixed meal in T2DM patients there is a paradoxical rise in plasma glucagon concentration which antagonizes the decline in HGP, resulting in postprandial hyperglycemia [360,361]. Thus, deranged glucagon secretion by the pancreatic α cell contributes to both fasting and postprandial hyperglycemia in T2DM patients.
The kidney: increased glucose reabsorption
The kidney filters ∼162 g ([glomerular filtration rate=180 L day−1] × [fasting plasma glucose = 900 mg L−1]) of glucose every day. Ninety percent of the filtered glucose is reabsorbed by the high capacity SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of the filtered glucose is reabsorbed by the SGLT1 transporter in the straight segment of the descending proximal tubule . The result is that no glucose appears in the urine.
In T1DM and T2DM animal models, the maximal renal tubular reabsorptive capacity (Tm) for glucose is increased [363–365]. In humans with T1DM  and T2DM  the Tm for glucose is increased, and cultured human proximal renal tubular cells from T2DM patients demonstrate markedly increased levels of SGLT2 mRNA and protein and a fourfold increase in the uptake of α-methyl-d-glucopyranoside (AMG), a nonmetabolizeable glucose analogue  (Figure 25.16). Thus, an adaptive response by the kidney to conserve glucose, which is essential to meet the energy demands of the body, especially the brain and other neural tissues, which have an obligate need for glucose, becomes maladaptive in the diabetic patient. Instead of dumping glucose in the urine to correct the hyperglycemia, the kidney chooses to hold on to the glucose. Even worse, the ability of the diabetic kidney to reabsorb glucose is augmented by an absolute increase in the renal reabsorptive capacity for glucose.
The brain, along with its seven companions, forms the eighth component of the Ominous Octet (Figure 25.17). The current epidemic of diabetes is being driven by the epidemic of obesity . Porte and colleagues [370–373] were amongst the first to demonstrate that, in rodents, insulin was a powerful appetite suppressant. Obese individuals, both diabetic and nondiabetic, have moderate-to-severe insulin resistance with compensatory hyperinsulinemia.Nonetheless, food intake is increased in obese subjects despite the presence of hyperinsulinemia which should suppress the appetite. Therefore, one could postulate that the insulin resistance in peripheral tissues also extends to the brain.
Using functional magnetic resonance imaging (MRI), the cerebral response to an ingested glucose load has been studied . After glucose ingestion, two hypothalamic areas with consistent inhibition have been noted: the lower posterior hypothalamus, which contains the ventromedial nuclei, and the upper posterior hypothalamus, which contains the paraventricular nuclei. In both of these hypothalamic areas, which are key centers for appetite regulation, the magnitude of the inhibitory response following glucose ingestion was reduced in obese, insulin-resistant, normal glucose-tolerant subjects, and there was a delay in the time taken to reach the maximum inhibitory response, even though the plasma insulin response was markedly increased in the obese group. Whether the impaired functional MRI response in obese subjects contributes to or is a consequence of the insulin resistance and weight gain remains to be determined. Nonetheless, these results suggest that the brain, like other organs (liver, muscle, and fat) in the body, are resistant to insulin. Studies by Obici et al. [375,376] and others  in rodents have also provided evidence for cerebral insulin resistance leading to increased HGP and reduced muscle glucose uptake.
Implications for therapy
The preceding review of the pathophysiology of T2DM has important therapeutic implications (Table 25.1). First, effective treatment of T2DM will require multiple drugs used in combination to correct the multiple pathophysiologic defects. Second, the treatment should be based upon reversal of known pathogenic abnormalities and NOT simply on the reduction in HbA1c. Third, therapy must be started early in the natural history of T2DM, if progressive β-cell failure is to be prevented. The treatment of T2DM is discussed in detail in Chapters 42–46 and 48.