Different effects of insulin and oral antidiabetic agents on glucose and energy metabolism in Type 2 (non-insulin-dependent) diabetes mellitus

Abstract

Which therapy should be used in Type 2 (non-insulin-dependent) diabetic patients with "secondary sulfonylurea failure", insulin or a combination of sulfonylurea and metformin? To address this question, we have compared the effect of 6 months of insulin therapy twice daily with that of a combination of glibenclamide and metformin in 24 Type 2 diabetic subjects, who no longer responded to treatment with sulfonylureas. Both treatments resulted in an equivalent 30% improvement in mean daily blood glucose (p less than 0.001), without significant effect on serum lipids. Insulin improved glycaemic control primarily by reducing basal hepatic glucose production (p less than 0.05), but had no significant effect on peripheral glucose metabolism. The combination of glibenclamide and metformin enhanced significantly total body glucose metabolism (p less than 0.05), predominantly by stimulating the non-oxidative pathway. Neither insulin nor the combination therapy altered B-cell response to a test meal. Insulin therapy resulted in a 6% increase in body weight, 63% of which was accounted for by increased fat mass. Although body weight was unchanged during sulfonylurea/metformin therapy, lean body mass and energy expenditure decreased significantly (p less than 0.05). We conclude that insulin and glibenclamide/metformin have different long-term effects on glucose and energy metabolism in Type 2 diabetes.

Use of a reference four-component model to define the effects of insulin treatment on body composition in type 2 diabetes: the ?Darwin study?

“…The components of this increased BWt have not been clearly defined; some studies have shown equal increases in fat and FFM [6], whereas others indicated the increase as predominantly FFM [5]. These discrepancies could result from differences in study populations (obese vs non-obese), insulin regimens (conventional vs intensive; continuous vs bolus) or the body composition methodology used (BIA [7][8][9], DXA [5,6] or tritiated water dilution [10]). In contrast, use of the 4-CM [13] in this clinical study provided accurately assessed characterisation of the composition of BWt increases in a group of type 2 diabetes patients from the start of insulin therapy, along with a number of other clinically relevant indices (Table 1), and assessment of BWt distribution through the complementary use of DXA estimates of segmental composition [17,19].…”

“…This differential body fat distribution could account for the beneficial effects of metformin in patients on insulin therapy [10,14,28,29]. Furthermore, patients who are losing significant BWt prior to insulin therapy may be more likely to gain BWt than those who are not.…”

“…However, many of the techniques used in these studies have not been specifically validated for use in type 2 diabetes patients and rely on assumptions that may be inappropriate in type 2 diabetes. Most [7][8][9] used bioelectrical impedance analysis (BIA), while others used dual energy X-ray absorptiometry (DXA [5,6]) or tritiated water [10]. No study has yet applied a reference method suitable for assessing key features or changes in the FFM, such as its hydration fraction (HF ffm ) or density (D ffm ).…”

“…No study has yet applied a reference method suitable for assessing key features or changes in the FFM, such as its hydration fraction (HF ffm ) or density (D ffm ). An increase in central fat mass has also been indicated [10], which is associated with cardiovascular disease and increased morbidity and mortality [11,12]. It is possible, therefore, that any increase in visceral fat deposition due to insulin treatment could offset the advantage of improved glycaemic control.…”

Changes in patient weight and the impact of antidiabetic therapy during the first 5 years after diagnosis of diabetes mellitus

“…It is commonly observed that treatment of type 2 diabetic patients with sulfonylureas [8][9][10] or insulin [10][11][12] is associated with weight gain. This effect of sulfonylureas and insulin could possibly aggravate the insulin-resistance syndrome associated with type 2 diabetes [2,13,14] and thereby counteract the otherwise beneficial effects of these agents.…”