In utero fetal malnutrition
Low birth weight is associated with the development of IGT and T2DM in a number of populations [153,154]. Developmental studies in animals and humans have demonstrated that poor nutrition and impaired fetal growth (small babies at birth) are associated with impaired insulin secretion and/or reduced β-cell mass. Fetal malnutrition can also lead to the development of insulin resistance later in life . One could hypothesize that an environmental influence, for example, impaired fetal nutrition leading to an acquired defect in insulin secretion or reduced β-cell mass, when superimposed on insulin resistance, could eventuate in T2DM later in life.Thus, during the normal aging process, with the onset of obesity, or with a worsening of the genetic component of the insulin resistance, the β cell would be called upon to augment its secretion of insulin to offset the defect in insulin action. If β-cell mass (or function) is reduced (or impaired) by an environmental insult during fetal life, this would lead to the development of IGT and eventually overt T2DM. Although such a defect would limit the maximum amount of insulin that could be secreted, it would not explain the progressive decline in insulin secretion in response to physiologic stimuli as individuals progress from NGT to IGT to overt T2DM mellitus.
Summary. Although insulin resistance in liver and muscle are well established early in the natural history of the disease, overt T2DM does not occur in the absence of progressive β-cell failure.
Insulin resistance and type 2 diabetes mellitus
In cross-sectional studies and long-term, prospective longitudinal studies hyperinsulinemia has been shown to precede the onset of T2DM in all ethnic populations with a high incidence of T2DM [1–3,156–164]. Studies utilizing the euglycemic insulin clamp, minimal model, and insulin suppression techniques have provided direct quantitative evidence that the progression from normal to impaired glucose tolerance is associated with the development of severe insulin resistance, whereas plasma insulin concentrations, both in the fasting state and in response to a glucose load (Figures 25.3 and 25.4) are increased when viewed in absolute terms (see earlier discussion about insulin secretion).
Himsworth and Kerr, using a combined oral glucose and i.v. insulin tolerance test, were the first to demonstrate that tissue sensitivity to insulin was diminished in type 2 diabetic patients . In 1975 Reaven and colleagues, using the insulin suppression test, provided further evidence that the ability of insulin to promote tissue glucose uptake in T2DM was severely reduced . A defect in insulin action in T2DM also has been demonstrated with the arterial infusion of insulin into the brachial artery (forearm muscle) and femoral artery (leg muscle), as well as with radioisotope turnover studies, the frequently sampled i.v. glucose tolerance test, and the minimal model technique [1–3,6,167–169].
DeFronzo et al., using the more physiologic euglycemic insulin clamp technique, have provided the most conclusive documentation that insulin resistance is a characteristic feature of lean, as well as obese, type 2 diabetic individuals [1–3,6,12,170,171]. Because diabetic patients with severe fasting hyperglycemia (>180–200 mg dL−1, 10.0–11.1mmol L−1) are insulinopenic (Figure 25.3), and because insulin deficiency is associated with the emergence of a number of intracellular defects in insulin action, these initial studies focused on diabetics with mild to modest elevations in the fasting plasma glucose concentration (mean=150±8mg dL−1, 8.3±0.4mmol L−1). Insulin-mediated whole-body glucose disposal in these lean diabetics was reduced by ∼40–50%, providing conclusive proof of the presence of moderate to severe insulin resistance. Three additional points are noteworthy: (i) lean type 2 diabetics with more severe fasting hyperglycemia (198±10mg dL−1) have a severity of insulin resistance that is only slightly (10–20%) greater than in diabetics with mild fasting hyperglycemia; (ii) the defect in insulin action is observed at all plasma insulin concentrations, spanning the physiologic and pharmacologic range (Figure 25.6); (iii) diabetic patients with overt fasting hyperglycemia can not elicit a normal glucose metabolic response to even maximally stimulating plasma insulin concentrations under euglycemic conditions. Virtually all investigators have demonstrated that lean type 2 diabetic subjects are resistant to the action of insulin [48,86,157–160,163,169,172–175].
The ability of glucose (hyperglycemia) to stimulate its own uptake, that is, the mass action effect of hyperglycemia, is also impaired in T2DM .
Site of insulin resistance in type 2 diabetes
Both the liver and muscle are severely resistant to insulin in individuals with T2DM (reviewed in [1–3]). However, when discussing insulin resistance, it is important to distinguish what is responsible for the insulin resistance in the basal or fasting state and what is responsible for the insulin resistance in the insulin-stimulated state.
The brain and all nueronal tissues have an obligate need for glucose and are responsible for ∼50% of glucose utilization under basal or fasting conditions [4,5]. This glucose demand is met primarily by glucose production by the liver (80–90%) and to a smaller extent by the kidneys . Following an overnight fast, the liver of nondiabetic individuals produces glucose at the rate of ∼2.0mg kg−1 per min [1–3,38] (Figure 25.7). In T2DM individuals, the basal rate HGP is increased, averaging ∼2.5mg kg−1 per min [1–3,38] (Figure 25.7). This amounts to the addition of an extra 25–30 g of glucose to the systemic circulation every night in a 80-kg person. In healthy control subjects the fasting plasma glucose concentration is ∼85–90 mg dL−1, and their basal rate of HGP averages ∼2mg kg−1 per min. In type 2 diabetic subjects, the fasting plasma glucose concentration rises in direct proportion to the increase in the basal rate of hepatic glucose production (r =0.847, p <0.001). This excessive production of glucose by the liver occurs despite fasting plasma insulin levels that are increased 2.5- to threefold, indicating severe resistance to the suppressive effect of insulin on HGP. Similar observations consistently have been made by others [40,177–181]. The increase in basal HGP is explained entirely by an increase in hepatic gluconeogenesis [182–184]. In addition to hepatic insulin resistance, multiple other factors contribute to the accelerated rate of basal HGP including: (i) increased circulating glucagon levels and enhanced hepatic sensitivity to glucagon [185–187]; (ii) lipotoxicity leading to increased expression and activity of phosphoenolpyruvate carboxykinase and pyruvate carboxylase , the rate-limiting enzymes for gluconeogenesis; and (iii) increased expression and activity of glucose-6-phosphatase, the rate-limiting enzyme for glucose escape from the liver. In rodents the increase G6Pase activity has been shown to result from glucotoxcity .
During a mixed meal or following glucose ingestion, the liver of type 2 diabetic patients is also resistant to the suppressive effect of insulin on HGP [40,190]. Using the euglycemic insulin clamp  in combination with isotopic glucose, the dose-response relationship between hepatic glucose production and the plasma insulin concentration has been examined  (Figure 25.8). The following points deserve emphasis: (i) the dose-response curve relating to inhibition of HGP to the plasma insulin level is very steep, with a half-maximal insulin concentration (ED50) of ∼30–40 μUmL−1; (ii) in type 2 diabetic subjects the dose-response curve is shifted rightward, indicating resistance to the inhibitory effect of insulin on hepatic glucose production. However, elevation of the plasma insulin concentration to the high physiologic range (∼100 μUmL−1) can overcome the hepatic insulin resistance and cause a near normal suppression of HGP; (iii) the severity of the hepatic insulin resistance is related to the level of glycemic control. In type 2 diabetic patients with mild fasting hyperglycemia, an increment in plasma insulin concentration of 100 μUmL−1 causes a complete suppression of HPG. However, in diabetic subjects with more severe fasting hyperglycemia, the ability of the same plasma insulin concentration to suppress HGP is impaired. These observations indicate that there is an acquired component of hepatic insulin resistance, which becomes progressively worse as the diabetic state decompensates over time.
The kidney possesses all of the gluconeogenesis enzymes required to produce glucose and estimates of the renal contribution to total endogenous glucose production have varied from 5% to 20% [192,193]. These varying estimates of the contribution of renal gluconeogenesis to total glucose production are, in large part, related to differences in the methodology employed to measure renal glucose production . One study suggests that the basal rate of renal gluconeogenesis is increased in type 2 diabetics and contributes to the elevation in fasting plasma glucose concentration . However, studies employing the hepatic vein catheter technique have shown that all of the increase in total body endogenous glucose production (measured with 3-3H-glucose) in type 2 diabetics can be accounted for by increased hepatic glucose output (measured by the hepatic vein catheter technique) .
Muscle is the major site of insulin-mediated glucose disposal in humans [1–3,6]. Using the euglycemic insulin clamp technique  in combination with tritiated glucose to measure total body glucose disposal [1–3,6,19,28,32,39,41,60,61,177,181,196–199], it has been conclusively demonstrated that lean type 2 diabetic individuals are severely resistant to insulin compared with age-, weight-, and sex-matched control subjects. Employing femoral arterial and venous catheterization in combination with the insulin clamp, muscle insulin resistance has been shown to account for over 85–90% of the impairment in total body glucose disposal in type 2 diabetic subjects [6,36] (Figure 25.9). There is a significant delay (20–30 min) in the muscle’s response to insulin. However, even if the insulin clamp is extended for an additional hour in diabetic subjects to account for the delay in onset of insulin action, the rate of insulin-stimulated glucose disposal remains 50% less than in control subjects. A similar defect in insulin-stimulated muscle glucose uptake in type 2 diabetic subjects has been demonstrated using the limb catheterization technique [36,200–203].
In type 2 diabetic subjects multiple intramyocellular defects in insulin action have been demonstrated (revised in [1–3,42]), including impaired glucose transport and phosphorylation [36,203–206], reduced glycogen synthesis [205–208], and decreased glucose oxidation [39,209]. However, more proximal defects in the insulin signal transduction system play a paramount role in the muscle insulin resistance [42,210,211].)
Insulin signal transduction.
For insulin to work, it must first bind to and then activate the insulin receptor by phosphorylating key tyrosine residues on the β chain [42,211–214] (Figure 25.10). This results in the translocation of insulin receptor substrate (IRS)-1 to the plasma membrane, where it interacts with the insulin receptor and also undergoes tyrosine phosphorylation. This leads to the activation of PI-3 kinase and Akt, resulting in glucose transport into the cell, activation of nitric oxide synthase with arterial vasodilation [215–217], and stimulation of multiple intracellular metabolic processes.
Studies by DeFronzo and colleagues were the first to demonstrate in humans that the ability of insulin to tyrosine phosphorylate IRS-1 was severely impaired in lean type 2 diabetic individuals [42,210,211,218], in obese normal glucose-tolerant individuals , and in the insulin-resistant, normal glucose-tolerant offspring of two type 2 diabetic parents  (Figure 25.11). Similar defects have been demonstrated by others in human muscle [37,220–223]. The defect in insulin signaling leads to decreased glucose transport, impaired release of nitric oxide with endothelial dysfunction, and multiple defects in intramyocellular glucose metabolism.
In contrast to the severe defect in IRS-1 activation, the mitogen-activated protein (MAP) kinase pathway, which can be activated by Shc, is normally responsive to insulin  (Figure 25.11). The MAP kinase pathway, when stimulated, leads to the activation of a number of intracellular pathways involved in inflammation, cellular proliferation, and atherosclerosis [211,224–226]. The block at the level of IRS-1 impairs glucose transport into the cell and the resultant hyperglycemia stimulates insulin secretion. Because the MAP kinase pathway retains its sensitivity to insulin [210,211,220,226], this causes excessive stimulation of this pathway and activation of multiple intracellular pathways involved in inflammation and atherogenesis. This, in part, may explain the strong association between insulin resistance and atherosclerotic cardiovascular disease in nondiabetic, as well as in type 2 diabetic, individuals [211,227–232]. The only class of oral antidiabetic drugs—the TZDs—that simultaneously augment insulin signaling through IRS-1 and inhibit the MAP kinase pathways is the thiazolidinediones .
Route of glucose administration: oral versus intravenous.
The euglycemic insulin clamp, by maintaining plasma glucose and insulin levels constant, has become the gold standard for quantitating insulin sensitivity. However, the normal route of glucose administration in everyday life is via the gastrointestinal tract. Using a double tracer technique (1-14C-glucose orally and 3-3H-glucose intravenously) in combination with hepatic vein catheterization, the disposal of oral versus i.v. glucose has been examined in healthy, normal glucose-tolerant and type 2 diabetic subjects [6,40,190,196,233]. Under basal conditions, with fasting plasma glucose and insulin concentrations of 90mg dL−1 and 11mUmL−1, respectively, the splanchnic tissues, which primarily reflect the liver, take up glucose at the rate of 0.5mg kg−1 per min (Figure 25.12). When insulin is administered intravenously in subjects with NGT to raise the plasma insulin concentration to 1189 μUmL−1 while maintaining euglycemia, no stimulation of hepatic glucose uptake is observed. When insulin is infused with glucose to elevate both glucose and insulin levels, hepatic glucose uptake is increased, but only in proportion to the increase in plasma glucose concentration, despite plasma insulin concentrations in excess of 1000 μUmL−1. In contrast, oral glucose administration augments hepatic glucose uptake 4.5-fold, despite plasma insulin and glucose concentrations that are much lower than with i.v. glucose plus insulin administration (Figure 25.12). If the same oral glucose load is administered to type 2 diabetic individuals, despite higher plasma glucose and insulin concentrations than in nondiabetic subjects, hepatic glucose uptake is reduced by >50%. These results indicate that T2DM individuals lack the gut factor responsible for enhancing hepatic glucose uptake following glucose ingestion.
In summary, impaired insulin secretion, decreased muscle glucose uptake, increased HGP, and decreased hepatic glucose uptake all contribute to the glucose intolerance in type 2 diabetic individuals.