NOCTURNAL AND POSTPRANDIAL METABOLISM IN DIABETES MELLITUS

with special reference to lipid intolerance and the second meal effect By Mette Axelsen, Lundberg Laboratory for Diabetes Research, Institute of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden

ABSTRACT

Diabetes mellitus is a rapidly growing global health problem. Modern, intensified therapy prevents or delays the microvascular complications in both Type 1 and Type 2 diabetic patients. However, intensified insulin therapy in Type 1 diabetes is associated with increased risk of serious nocturnal hypoglycemia. In contrast, fasting hyperglycemia, rather than hypoglycemia, is a major problem in Type 2 diabetes. One reason for this is that the nocturnal plasma free fatty acid (FFA) levels, which enhance the hepatic glucose production, are elevated. Around 40% of these patients have established macroangiopathy already at the onset of the disease. Thus, it is critically important to define early risk factors for cardiovascular disease and that effective stategies for the prevention of both macrovascular and microvascular complications are developed. The present study evaluated the potential beneficial effects of bedtime ingestion of a slowly digestible carbohydrate (uncooked cornstarch) on nocturnal and morning postprandial blood glucose control and lipid levels in Type 1 and Type 2 diabetic patients. Insulin sensitivity and postprandial triglyceride (TG) levels were also studied in healthy, normoglycemic individuals with a massive heredity for Type 2 diabetes. Bedtime uncooked cornstarch exhibited a lente release profile, the peak effect on nocturnal blood glucose being similar to the peak effect of NPH insulin, ie, after ~4 hrs. In Type 1 diabetics, bedtime ingestion of ~20 g of cornstarch led to a 70% reduction of nocturnal hypoglycemia without altering HbA1c or fasting lipid levels. In Type 2 diabetes, bedtime uncooked cornstarch ingestion led to sustained nocturnal insulinization and FFA suppression. This was associated with improved fasting blood glucose levels and glucose tolerance after breakfast, consistent with an overnight second-meal effect. The same effect was not obtained with similar amounts of rapid carbohydrates. The insulin secretory response during breakfast also tended to be improved. In contrast, the postprandial lipemia was not improved, probably because insulin resistance was not alleviated. It was also demonstrated, for the first time, that normoglycemic and normolipemic first-degree relatives of Type 2 diabetic patients, exhibit lipid intolerance in that the postprandial TG response to a fat-rich meal was ~50% higher. This, in turn, suggests that an atherogenic lipid profile is present already at this stage. In conclusion, bedtime ingestion of uncooked cornstarch seems to be a feasible tool to balance the effect of NPH insulin and, thus, to prevent nocturnal hypoglycemia in intensively treated Type 1 diabetic patients. Moreover, modulation of nocturnal plasma insulin and FFA levels by slow-release cornstarch can improve the morning glycemic control, possible due to relief of the "lipotoxic effect" of FFA on the ß-cell. The finding of a lipid intolerance in healthy subjects with massive heredity for Type 2 diabetes is a marker of an atherogenic lipid profile which obviously can be present long before glucose tolerance is impaired. Key words: diabetes, first-degree relatives, nocturnal, postprandial, glucose, triglyceride, metabolism, free fatty acids (FFA), insulin, insulin resistance, C-peptide, carbohydrates

ISBN: 91-628-3492-4. Göteborg 1999.

NOCTURNAL AND POSTPRANDIAL METABOLISM IN DIABETES MELLITUS
with special reference to lipid intolerance and the second meal effect

AKADEMISK AVHANDLING
som för avläggande av medicine doktors examen vid Göteborgs Universitet kommer att offentligen försvaras i Aulan, Sahlgrenska Universitetssjukhuset, Sahlgrenska, Göteborg Torsdagen den 8 april 1999 kl. 13.00 av Mette Axelsen, Klinisk näringsfysiolog

Fakultetsopponent: David Jenkins, Toronto, Canada Avhandlingen baseras på följande arbeten:

I. M Axelsen, C Wesslau, P Lönnroth, R Arvidsson Lenner & U Smith. Bedtime uncooked cornstarch supplement prevents nocturnal hypoglycemia in intensively treated IDDM subjects. J Internal Med 1999:249: in press.

II. M Axelsen, P Lönnroth, R Arvidsson Lenner & U Smith. Suppression of nocturnal free fatty acid levels by bedtime cornstarch in NIDDM subjects. Eur J Clin Invest 1997: 27:157-163.

III. M Axelsen, P Lönnroth, R Arvidsson Lenner, M-R Taskinen & U Smith. Suppression of nocturnal FFA levels by bedtime carbohydrate supplement in Type 2 diabetes: Effects on insulin sensitivity, lipids and glycemic control. Submitted.

IV. M Axelsen, R Arvidsson Lenner, P Lönnroth & U Smith. Breakfast glycemic response in patients with type 2 diabetes: Effects of bedtime dietary carbohydrates. Eur J Clin Nutr 1999: in press.

V. M Axelsen, U Smith, JW Eriksson, M-R Taskinen & P-A Jansson. Postprandial hypertriglyceridemia in normoglycemic first-degree relatives of patients with Type 2 diabetes. Submitted.