One key reason underlying the profound postprandial hyperglycemia observed in patients with T2DM is a decrease in the peripheral uptake of glucose. In response to increasing insulin levels in normal individuals as well as those with T2DM, peripheral uptake of glucose occurs; however, the efficiency of uptake in patients with T2DM is markedly reduced. A study
8 evaluating the rate of total body glucose disposal as a function of increasing insulin concentrations showed the rate of glucose uptake was reduced by about 30% in patients with T2DM, compared with control patients, at the two highest concentrations of insulin (
P<.01). The same study
8 also demonstrated that basal hepatic glucose production (HGP) was significantly greater in patients with T2DM than in control subjects (mean [SD], 83 [4] vs 71 [2] mg/mg
2/min;
P<.01). Fasting plasma glucose (FPG) was also significantly correlated with basal HGP (
r=0.82;
P<.01).
8 These findings suggest that the level of insulin production achieved in a patient with T2DM is insufficient to control hyperglycemia.
Patients with T2DM also have a reduced uptake of glucose into cells, less efficient shunting of glucose into key metabolic pathways such as the tricarboxylic acid cycle, and less storage of glycogen.
9,10 In one series of glucose clamping experiments, an impaired rate of glucose disposal was shown in patients with T2DM as well as in those with IGT.
9 Mean rates of glucose disposal in both groups were significantly less compared with control subjects (
P<.01).
9 Results from these studies also suggested a spectrum of defects in patients with varying degrees of glucose intolerance, including reduced insulin receptor expression and defects in the postreceptor actions of insulin.
9 Thus, patients with T2DM may have impairment in glucose uptake mechanisms and in the utilization and disposal of excess glucose once inside the cell. Glucose stays elevated in the periphery because insulin-stimulated glucose uptake—as well as insulin-stimulated glycogen synthesis—are reduced.
A key reason for postprandial glucose elevation in T2DM relates to the blunted glucose-stimulated production of insulin. While many potential mechanisms may account for this phenomenon, the reduction of pancreatic β-cell mass in patients with T2DM is worth noting. Results from autopsy studies of obese individuals characterized as having either normal glucose tolerance (NGT, n=31), impaired fasting glucose (IFG, n=19), or T2DM (n=41) showed that, with progression from NGT to IFG to T2DM, β-cell masses progressively decrease (
Figure 3).
11 Patients with IFG had a 40% decrease in relative β-cell volume (
P<.05), whereas those with T2DM had a 63% decrease, compared to the NGT group (
P<.01).
11 The authors concluded that obese and lean patients with T2DM experience a loss of β-cell volume, and, presumptively, β-cell mass, compared to their nondiabetic weight- and age-matched cohorts. The mechanism of this loss was attributed to an increase in β-cell apoptosis when compared to a change in the rate of new islet formation.
11
The progression from NGT to IGT in this study
11 is noteworthy for physicians because patients with glucose levels of 102 to 111 mg/dL would ordinarily not arouse much concern, yet these patients would have already lost about 40% of their β-cell mass. By the time T2DM was diagnosed, the loss would be at least 60%.
11 Thus, one reason for low insulin and, consequently, hyperglycemia, in patients with T2DM is the progressive loss of pancreatic β cells.
Similar results have been reported in other clinical trials, in which not only has pancreatic islet cell mass decreased in patients with T2DM, but the remaining islets do not function properly. Islets from the pancreas of cadaveric T2DM (n=14) and normal cadaveric donors (n=14) were isolated and matched for age, body mass index, and cold ischemia time. A significant difference in islet cell mass between patients with T2DM and normal donors (256,260 vs 597,569 islet equivalents, respectively;
P<.001) was observed, which showed significantly reduced islet cell mass in patients with T2DM.
12 Moreover, patients with T2DM had poorer islet function compared to controls. The threshold for glucose-stimulated insulin release (GSIR) was 7 and 12 mmol/L in normal vs diabetic islets, and the GSIR peak rate of normal subjects was twice that of patients with T2DM, demonstrating a poorer sensitivity to glucose.
12 These results suggest a loss of islet mass and an apparent decline in islet cell function in patients with T2DM.