Effects of Intensive Therapy and Antecedent Hypoglycemia on Counterregulatory Responses to Hypoglycemia in Type 2 Diabetes

Abstract

OBJECTIVE-The physiology of counterregulatory responses during hypoglycemia in intensively treated type 2 diabetic subjects is largely unknown. Therefore, the specific aims of the study tested the hypothesis that 1) 6 months of intensive therapy to lower A1C Ͻ7.0% would blunt autonomic nervous system (ANS) responses to hypoglycemia, and 2) antecedent hypoglycemia will result in counterregulatory failure during subsequent hypoglycemia in patients with suboptimal and good glycemic control.RESEARCH DESIGN AND METHODS-Fifteen type 2 diabetic patients (8 men/7 women) underwent 6-month combination therapy of metformin, glipizide XL, and acarbose to lower A1C to 6.7% and 2-day repeated hypoglycemic clamp studies before and after intensive therapy. A control group of eight nondiabetic subjects participated in a single 2-day repeated hypoglycemic clamp study.RESULTS-Six-month therapy reduced A1C from 10.2 Ϯ 0.5 to 6.7 Ϯ 0.3%. Rates of hypoglycemia increased to 3.2 episodes per patient/month by study end. Hypoglycemia (3.3 Ϯ 0.1 mmol/l) and insulinemia (1,722 Ϯ 198 pmol/l) were similar during all clamp studies. Intensive therapy reduced (P Ͻ 0.05) ANS and metabolic counterregulatory responses during hypoglycemia. Antecedent hypoglycemia produced widespread blunting (P Ͻ 0.05) of neuroendocrine, ANS, and metabolic counterregulatory responses during subsequent hypoglycemia before and after intensive therapy in type 2 diabetic patients and in nondiabetic control subjects.CONCLUSIONS-Intensive oral combination therapy and antecedent hypoglycemia both blunt physiological defenses against subsequent hypoglycemia in type 2 diabetes. Prior hypoglycemia of only 3.3 Ϯ 0.1 mmol/l can result in counterregulatory failure in type 2 diabetic patients with suboptimal control and can further impair physiological defenses against hypoglycemia in intensively treated type 2 diabetes. Diabetes 58:701-709, 2009 L arge randomized controlled multicenter clinical trials have demonstrated the benefit of improved glycemic control on microvascular complications in both type 1 and type 2 diabetes (1,2). These compelling data have produced a paradigm shift in the treatment of diabetes (particularly type 2 diabetes) striving for A1C values Ͻ7.0% (3). The major drawbacks of tight metabolic control in patients with type 1 diabetes are well documented and include increased hypoglycemia and weight gain (4 -8).Recently, three large studies have investigated the effects of rigorous metabolic control (A1C Ͻ7.0%) on the prevalence of macrovascular disease in type 2 diabetes (9 -11). The overall conclusion of these studies was that A1C values Ͻ7.0% did not produce a statistically significant reduction in macrovascular events but did produce a marked increase in hypoglycemia in type 2 diabetes. The effects of intensive therapy on physiological counterregulatory responses during hypoglycemia in type 2 diabetes have not been thoroughly investigated. Burge et al. (12) demonstrated that improving glycemic control during an 8-day in-patient admission could lower sy...

Repetitive hypoglycaemia increases serum adrenaline and induces monocyte adhesion to the endothelium in rat thoracic aorta

“…Recently, the counter-regulatory response to repetitive hypoglycaemia was investigated in intensive treatment of type 2 diabetes [24]. Repeated episodes of relatively mild hypoglycaemia reduced the counter-regulatory responses and impaired physiological defences against hypoglycaemia.…”

Diabetic Gastrointestinal Neuropathy: Elusive Diagnosis and Difficult Treatment

“…Often the symptoms are elusive and the outstanding manifestation is a mindboggling glucose instability with unexpected peaks at any time of the day and unexplained *Address correspondence to this author at the Diabetes and Endocrinology Unit -ASL RMH, Italy; Tel:+390693273094; Fax:+39063218855; E-mails: info@patriziotatti.it, tatti0@tin.it and unpredictable hypoglycemic episodes that impact on the life of the patient and his family [5]. Hypoglycemia is a serious limiting factor for the intensive treatment of hyperglycemia at any age [6,7]. Beyond its ravaging consequences GI neuropathy may be a marker of other neuropathies and diabetic complications.…”

Hypoglycaemia in Type 2 diabetes

“…Davis et al reported equivalent reductions in adrenaline and symptomatic responses following antecedent hypoglycaemia as those seen in Type 1 diabetes. [22] Korzon-Borakowska et al [23] measured physiological responses before and after a period of tightening glycaemic control and demonstrated a lowering of the glycaemic thresholds for adrenaline and symptoms and a reduced adrenaline response. It therefore seems likely that tightening control might lead to a re-setting of protective physiological responses at a lower blood glucose.…”