To test the hypothesis that the neuroendocrine (including autonomic) responses to hypoglycemia are dissociated from the symptomatic responses to hypoglycemia in insulin-dependent diabetes mellitus (IDDM) patients with hypoglycemia awareness and during reversal of hypoglycemia unawareness in IDDM, we used the hyperinsulinemic stepped hypoglycemic (5.0, 4.4, 3.9, 3.3, 2.8, and 2.2 mmol/l) clamp technique to quantitate these responses in nondiabetic control subjects and IDDM patients with hypoglycemia awareness and with hypoglycemia unawareness. The latter were restudied after 3 days, 3-4 weeks, and 3 months of scrupulous avoidance of iatrogenic hypoglycemia. At baseline, symptom responses were virtually nil in unaware patients (P = 0.0001 vs. nondiabetic); these were increased in aware patients (P = 0.0183 vs. nondiabetic). In contrast, several neuroendocrine responses were comparably reduced in both unaware and aware patients: epinephrine (P = 0.0222 and 0.0156), pancreatic polypeptide (P = 0.0004 and 0.0003), glucagon (P = 0.0112 and 0.0109), and cortisol (P = 0.0214 and 0.0450). In initially unaware patients, symptom responses increased (P = 0.0001) during avoidance of hypoglycemia. Demonstrable after 3 days, these were entirely normal after 3-4 weeks and 3 months. In contrast, none of the neuroendocrine responses increased. Thus, we conclude that several neuroendocrine responses to hypoglycemia (including the adrenomedullary and parasympathetic components of the autonomic response) can be dissociated from symptomatic responses in IDDM patients with hypoglycemia awareness and during reversal of hypoglycemia unawareness in IDDM. Avoidance of iatrogenic hypoglycemia sufficient to reverse the clinical syndrome of hypoglycemia unawareness did not reverse the key elements (deficient glucagon and epinephrine responses) of the clinical syndrome of defective glucose counterregulation. This implies that the mechanisms of hypoglycemia unawareness and of defective glucose counterregulation are, at least in part, different in IDDM.
The euglycemic hyperglycemic clamp is generally regarded as a reference method for assessing insulin sensitivity. However, this method is laborious and expensive. The oral glucose tolerance test (OGTT), the most commonly used method for evaluating whole body glucose tolerance, has often been used to assess insulin sensitivity. In the previous studies the correlation between the insulin sensitivity index (ISI) obtained from the OGTT (ISI(OGTT)) and those obtained from the glucose clamp (ISI(Clamp)) may not be satisfactory. This is because the glucose clamp study is designed for measuring peripheral glucose utilization, whereas plasma glucose responses during the OGTT are the results of peripheral glucose utilization and hepatic glucose production. Based on this problem, we developed a new equation, ISI(OGTT), [1.9/6 x body weight (kg) x fasting plasma glucose (mmol/liter) + 520 - 1.9/18 x body weight x area under the glucose curve (mmol/h.liter) - urinary glucose (mmol)/1.8] / [area under the insulin curve (pmol/h.liter) x body weight], which would represent peripheral glucose utilization only. We tested our equation with ISI(Clamp) and also compared with others. Thirty-three healthy volunteers (16 males) with normal glucose tolerance underwent a 75-g, 3-h OGTT on the morning of d 1 and a glucose clamp on the morning of d 2. Their mean (+/-SD) age and body mass index were 30.8 +/- 8.3 yr and 22.0 +/- 3.9 kg/m(2), respectively. The mean (+/-SD) glucose disposal rate and ISI determined by glucose clamp were 27.46 +/- 16.55 micro mol/kg.min and 7.39 +/- 2.72 micro mol/kg.min/pmol.liter, respectively. Pearson's correlation coefficient between our ISI(OGTT) and ISI(Clamp) was 0.869 (P < 0.0001) which was stronger than those corresponding values calculated from HOMA, QUICKI, Belfiore, Cederholm, Gutt, Matsuda, and Stumvoll, the respective values of which were 0.404, 0.434, 0.643, 0.533, 0.584, 0.734, and 0.508. In conclusion, the ISI(OGTT) derived from our equation is more suitable than others in assessing insulin sensitivity in subjects with normal glucose tolerance. Further studies in subjects with impaired glucose tolerance and diabetes mellitus should be performed to confirm the validity of this equation.
Type 2 DM is a significant risk factor for root surface, but not for coronal caries. Periodontal disease should be treated early in type 2 diabetic subjects to reduce the risk of subsequent root surface caries.
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