Studies on Plasma Glucagon Concentration in Maturity-Onset Diabetics with Autonomic Neuropathy

Abstract

The mean fasting plasma immunoreactive glucagon (IRG) concentration in 25 non-insulin-dependent, maturity-onset diabetics (MODs) was 15.4 ± 3.1 pmol/L, which was not significantly different from the 16.8 ± 2.4 pmol/L in 17 normal controls of similar age. However, in seven MODs with autonomic neuropathy (AN) the mean fasting IRG concentration of 44.7 ± 4.4 was significantly greater than the 17.4 ±1.3 pmol/L in 18 MODs without neuropathy and compared with controls. We, therefore, investigated IRG concentrations in five age-matched, non-insulin-dependent MODs with AN and five without it. Plasma IRG concentrations were measured in the basal state on three separate occasions and in response to insulin and to a mixed meal. Fasting or basal IRG concentrations were measured in the morning with and without a preceding 12-h insulin infusion to determine the effects of reduction in fasting plasma glucose concentrations and after 12 h of nasogastric aspiration to exclude continued stimulation caused by delayed gastric emptying. In the select group of Subjects the mean basal plasma IRG concentration was raised above the normal in diabetics with AN (49.4 ± 5.1) and was 16.2 ± 2.1 in diabetics without AN, which was within normal limits. Neither 12 h of insulin infusion (0.5–0.8 U/h) nor 12 h of nasogastric aspiration altered basal IRG concentrations in either group. The maximum incremental IRG response to acute insulin administration (0.2 U/kg) in diabetics with AN was 6.8 ± 3.9, which was significantly impaired compared with 24.9 ± 4.8 in nine MODs without AN and with 26.3 ± 6.7 in five normal controls. The maximum increment in IRG response to acute insulin administration in diabetics with AN rose significantly to 32.8 ± 12.9 after 12 h of insulin infusion. Although the maximum IRG responses to a mixed meal were higher in both diabetic groups than in the normal controls, there was a delayed initial rise and persistent elevation in diabetics with AN. We suggest that (1) basal IRG concentrations may be dependent on the integrity of the autonomic nervous system in MODs; (2) MODs without AN seem to have a normal response to insulin-induced hypoglycemia, whereas in MODs with AN the response is impaired and can be corrected by an adequate degree of both insulinization and reduction in fasting blood glucose concentration; and (3) the maximum IRG response to a mixed meal is exaggerated in all MODs and is not dependent on the integrity of the autonomic nervous system, although the pattern of response may be altered in the presence Of AN.

Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.

“…In the four previous studies that we are aware of that dealt with this issue, (3,(13)(14)(15), no consensus was reached concerning the appropriateness of counterregulatory hormone responses (3,(13)(14)(15). Furthermore, no data are presently available concerning changes in glucose production and glucose utilization or the ability to restore euglycemia.…”

Glucose counterregulation in Type 2 diabetes mellitus

“…All papers concerning glucose counterregulatory hormone responses to hypoglycaemia in Type 2 DM were regarded eligible for evaluation in this review. We were able to retrieve 16 research articles [23–37,39], the characteristics of which are shown in Table 2. From the study by Polonsky et al .…”

“…From another study [34], investigating counterregulatory responses to hypoglycaemia in Type 2 diabetic patients before and after intensified metabolic control, only data after improved control are shown. In 12 studies [24–32,34,35,37], metabolic responses to hypoglycaemia were compared between Type 2 DM and healthy controls, which form the focus of this review.…”

“…Finally, hypoglycaemia associated with oral agents, particularly glibenclamide and chlorpropamide [19–21], may be very persistent and occasionally lethal [22]. Relatively little is known about the integrity of counterregulation in patients with Type 2 DM and its role in the vulnerability to hypoglycaemia [23–37]. Since tight metabolic control is being increasingly advocated in Type 2 DM [38], it is important to understand whether impaired glucose counterregulation might limit its implementation.…”

Practical strategies to normalize hyperglycemia without undue hypoglycemia in type 2 diabetes mellitus

“…It is not clear whether the presence of autonomic failure secondary to advanced diabetic neuropathy predisposes to hypoglycemia. A reduced glucagon response has been seen in patients with type 2 diabetes and autonomic neuropathy compared to those without autonomic neuropathy; however, it is possible that more advanced islet cell failure could have contributed to this as well [ 19 ].…”