Hypoglycaemia and counterregulation in type 2 diabetes
Authors: John E Gerich
Journal: The Lancet (2000)

Several landmark clinical trials—the Diabetes Control and Complications Trial,1DCCT Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (23301) Google Scholar the Kuomomoto Study,2Ohkubo Y Kishikawa H Araki E et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract. 1995; 28: 103-117Summary Full Text PDF PubMed Scopus (2901) Google Scholar the UK Prospective Diabetes Study,3UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Summary Full Text Full Text PDF PubMed Scopus (19415) Google Scholar and the Stockholm Study4Reichard P Pihl M Rosenqvist U Sule J Complications in IDDM are caused by elevated blood glucose level: the Stockholm Diabetes Intervention Study (SDIS) at 10-year follow up.Diabetologia. 1996; 39: 1483-1488Crossref PubMed Scopus (150) Google Scholar—have demonstrated that strict control of blood-glucose (HbAlc less than 7·0%, or a value less than 1% above the normal range) can prevent the onset and slow the progression of long-term complications in both type 1 and type 2 diabetes. For many patients, however, treatment-related hypoglycaemia (or fear of it) hinders achievement of ideal control.5Cryer P Banting Lecture: Hypoglycemia, the limiting factor in the management of IDDM.Diabetes. 1994; 43: 1378-1389Crossref PubMed Google Scholar In two of the above studies1DCCT Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (23301) Google Scholar, 6Reichard P Pihl M Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study.Diabetes. 1994; 43: 313-317Crossref PubMed Google Scholar the risk of severe hypoglycaemia was about three times higher in patients with type 1 diabetes during intensive insulin treatment than in patients on conventional insulin regimens. Although still a problem, the increased risk of severe hypoglycaemia in patients with type 2 diabetes who are intensively treated with insulin seems to be much lower than it is with type 1. In the Japanese study2Ohkubo Y Kishikawa H Araki E et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract. 1995; 28: 103-117Summary Full Text PDF PubMed Scopus (2901) Google Scholar no severe hypoglycaemia was observed; and in the UK study,3UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Summary Full Text Full Text PDF PubMed Scopus (19415) Google Scholar the Veterans Cooperative Study7Abraira C Colwell J Nuttall F et al.VA CSDM GroupVeterans Affairs cooperative study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial.Diabetes Care. 1995; 18: 1113-1123Crossref PubMed Scopus (378) Google Scholar and the Veterans Implantable Insulin Pump Study8Saudek C Duckworth W Giobbie-Hurder A et al.Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial.JAMA. 1996; 276: 1322-1327Crossref PubMed Google Scholar severe hypoglycaemia was reported to occur at rates of 2·3, 3·0, and 7·8 per 100 patient-years respectively, compared with 62 per 100 patient-years in the DCCT.1DCCT Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (23301) Google Scholar Rates of severe hypoglycaemia among sulphonylurea users generally average less than 2% per year.9van Staa T Abenhaim L Monette J Rates of hypoglycemia in users of sulfonylureas.J Clin Epidemiol. 1997; 50: 735-741Summary Full Text PDF PubMed Scopus (187) Google Scholar Several factors may explain why patients with type 2 diabetes are less prone to severe hypoglycaemia. Normally as plasma glucose concentrations fall there is a hierarchy of defensive responses.5Cryer P Banting Lecture: Hypoglycemia, the limiting factor in the management of IDDM.Diabetes. 1994; 43: 1378-1389Crossref PubMed Google Scholar, 10Mitrakou A Ryan C Veneman T et al.Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction.Am J Physiol. 1991; 260: E67-E74PubMed Google Scholar The first is an increase in the release of counterregulatory hormones as plasma glucose falls to about 3·8 mmol/L; this response would prevent glucose concentrations from falling even further. The second is an awareness of warning symptoms, predominantly autonomic (sweating, hunger, anxiety, tachycardia), which begin as plasma glucose concentrations decrease to about 3·4 mmol/L. In experienced patients such symptoms will prompt preventive steps (eg, ingestion of carbohydrate) before neuroglycopenia occurs at around 3·0 mmol/L. In people who have had type 1 diabetes for over 5 years, counterregulatory hormone responses to hypoglycaemia are generally impaired.11Gerich J Bolli G Counterregulatory failure.in: Frier BM Fisher M Hypoglycaemia and diabetes. Edward Arnold, London1993: 253-267Google Scholar Initially most patients lose their glucagon response to hypoglycaemia, thereby becoming dependent on catecholamine responses to prevent or reverse hypoglycaemia. Sometimes even that response becomes impaired and the risk of severe hypoglycaemia increases several-fold.12White N Skor D Cryer P Bier D Levandoski L Santiago J Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy.N Engl J Med. 1983; 308: 485-491Crossref PubMed Scopus (312) Google Scholar Additionally, episodes of mild, even symptomless, hypoglycaemia can further impair glucose counterregulation13Veneman T Mitrakou A Mokan M Cryer P Gerich J Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia.Diabetes. 1993; 42: 1233-1237Crossref PubMed Google Scholar and reduce β-adrenergic sensitivity,14Fritsche A Stumvoll M Grub M et al.Effect of hypoglycemia on badrenergic sensitivity in normal and type 1 diabetic subjects.Diabetes Care. 1998; 21: 1505-1510Crossref PubMed Scopus (48) Google Scholar leading to a situation called hypoglycaemia unawareness,15Gerich J Mokan M Veneman T Korytkowski M Mitrakou A Hypoglycemia unawareness.Endocrine Rev. 1991; 12: 356-371Crossref PubMed Scopus (209) Google Scholar in which patients may not recognise impending hypoglycaemia until it is too late to be prevented. The situation is different in type 2 diabetes. First of all, although glucagon responses are commonly impaired,16Bolli G Tsalikian E Haymond M Cryer P Gerich J Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus.J Clin Invest. 1984; 73: 1532-1541Crossref PubMed Scopus (109) Google Scholar, 17Shamoon H Friedman S Canton C Zacharowicz L Hu M Rossetti L Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.J Clin Invest. 1994; 93: 2562-2571Crossref PubMed Scopus (64) Google Scholar catecholamine responses are usually normal18Levy C Kinsley B Bajaj M Simonson D Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM.Diabetes Care. 1998; 21: 1330-1338Crossref PubMed Scopus (66) Google Scholar or increased.16Bolli G Tsalikian E Haymond M Cryer P Gerich J Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus.J Clin Invest. 1984; 73: 1532-1541Crossref PubMed Scopus (109) Google Scholar, 17Shamoon H Friedman S Canton C Zacharowicz L Hu M Rossetti L Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.J Clin Invest. 1994; 93: 2562-2571Crossref PubMed Scopus (64) Google Scholar Second, the patients are insulin resistant. Third, they have persistent β-cell function. The ability to modulate insulin secretion can act as a buffer since endogenous insulin secretion will decrease as plasma glucose falls;16Bolli G Tsalikian E Haymond M Cryer P Gerich J Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus.J Clin Invest. 1984; 73: 1532-1541Crossref PubMed Scopus (109) Google Scholar this opportunity is not available to type 1 patients whose insulin availability is predetermined by the amount already injected. Fourth, most type 2 patients are not on intensive insulin regimens, so they are less at risk of hypoglycaemia unawareness as a result of insulin reactions. Finally, of all the oral agents used to treat type 2 diabetes, only insulin secretogogues (sulphonylureas such as glyburide and meglitinides such as repazlinide) have hypoglycaemia as a recognized side-effect. The report in this weeks's Lancet by Gill Spyer and colleagues provides further insight into the mechanism for the difference in the propensity between patients with type 1 and type 2 diabetes to develop severe hypoglycaemia. These investigators report that patients with type 2 diabetes of short known duration (5 years or less) who were reasonably well controlled by diet and/or oral agents (average HBA1C 1·9% above normal upper limit) have increases in counterregulatory hormone secretion and get symptoms at higher blood glucose concentrations than do non-diabetic controls. Although only seven patients were studied, these findings seem to describe a real phenomenon since they are similar to those of Meneilly et al19Meneilly G Cheung E Tuokko H Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes.Diabetes. 1994; 43: 403-410Crossref PubMed Google Scholar who studied ten elderly type 2 diabetic patients with an average known duration of 5 years who were well controlled (average HBA1C 6·9%, upper limit of normal 6·4%) by diet and/or oral agents. These investigators found that the diabetic patients had reduced glucagon responses, increased epinephrine responses that began at higher than normal plasma glucose concentrations, and increased cortisol responses. However, unlike the data reported today, there was no difference in either magnitude or threshold for symptoms which Spyer and colleagues attributed to reduced β-adrenergic sensitivity that occurs with ageing. Previous studies had shown decreased thresholds for initiation of counterregulation and symptoms in poorly controlled patients.20Korzon-Burakowska A Hopkins D Matyka K et al.Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes.Diabetes Care. 1998; 21: 283-290Crossref PubMed Scopus (72) Google Scholar, 21Boyle P Schwartz N Shah S Clutter W Cryer P Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics.N Engl J Med. 1988; 318: 1487-1492Crossref PubMed Scopus (264) Google Scholar Thus the key finding of Spyer et al is that these can also occur in well-controlled type 2 patients, which clearly differentiates such patients from those with type 1 and which should provide added protection against severe hypoglycaemia. At least two questions come to mind: is this protective alteration in threshold maintained with type 2 diabetes of longer duration, and is it modified by use of insulin to achieve good glycaemic control? Hepburn et al22Hepburn D MacLeod K Pell A Scougal I Frier B Frequency and Symptoms of hypoglycemia experienced by patients with type 2 diabetes treated with insulin.Diab Med. 1993; 10: 231-237Crossref PubMed Scopus (140) Google Scholar have reported that the frequency of severe hypoglycaemia is not significantly different in insulin-treated type 2 patients (mean known duration 12 years) and in type 1 patients matched for duration of insulin treatment and having similar HbA1c levels. Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetesGlucose thresholds for counter-regulatory hormone secretion are altered in well controlled type-2 diabetic patients, so that both symptoms and counter-regulatory hormone release can take place at normal glucose values. This effect might protect type-2 diabetic patients against episodes of profound hypoglycaemia and make the achievement of normoglycaemia more challenging in clinical practice. Full-Text PDF