At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of β3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications. Arch Intern Med. 1997;157:1802-1817

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=intemed&articleId=623758&pdfFileName=archinte_157_16_004.pdf

Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions.

This review considers the acute and chronic effects of different levels of carbohydrate (CHO) intakes. The type of CHO consumed, especially glucose vs fructose, affects the glycaemic, insulinaemic and thermogenic responses. In addition, other aspects of food (type of starch, method of processing or cooking, presence of other nutrients) affects the glycaemic response (glycaemic index). In general, the greatest benefit to health is derived from consuming foods with a low glycaemic index and a high non-starch polysaccharide (fibre) content. Healthy, moderately active adults require at least 200g CHO per day to sustain normal brain metabolism and muscle function. Moreover, the CHO content should represent at least 50% of energy intake. Higher intakes of CHO can have deleterious effects on blood lipids (especially plasma triacylglycerol) in middle-aged and elderly subjects, and are really only appropriate for subjects with a high level of physical activity who need to maintain muscle glycogen content. Meals with a high carbohydrate content can lead to problems of postprandial hypotension in the elderly, and impaired exercise capacity in patients with angina.

Carbohydrate as a nutrient in adults: range of acceptable intakes.

To gain insight into the pathophysiology of impaired glucose tolerance in pancreas transplantation, glucose kinetics and insulin secretion were assessed after an oral glucose load in four combined pancreas-kidney recipients with impaired glucose tolerance (IPx), in five combined pancreas-kidney recipients with normal glucose tolerance, in six nondiabetic kidney transplant recipients, and in eight normal subjects employing a dual isotope technique. β-Cell function was evaluated by calculating prehepatic insulin secretion rates, which subsequently were correlated to the ambient glucose concentrations to obtain an index of β-cell responsiveness. Oxidative and nonoxidative glucose metabolism were assessed by indirect calorimetry. Basal insulin secretion rates, the glucose-stimulated early insulin secretion rates, as well as β-cell responsiveness were markedly reduced in IPx than in the glucose-tolerant transplant subjects. Total systemic glucose appearance was similar in the groups with apparently comparable ...

/pdf/metabolism-of-oral-glucose-in-pancreas-transplant-recipients-3wx87q8l56.pdf

Metabolism of oral glucose in pancreas transplant recipients with normal and impaired glucose tolerance.

OBJECTIVE To examine the contribution of obesity to insulin resistance and abnormalities of intracellular glucose and fat metabolism in NIDDM. RESEARCH DESIGN AND METHODS Glucose turnover measurements and indirect calorimetry were performed in 10 obese non-insulin-dependent diabetes mellitus (NIDDM) and 10 lean NIDDM subjects (body mass index 35.3 ± 1.0 vs. 24.1 ± 0.5 kg/m 2 P -2 · min -1 ) euglycemic (5.0-5.5 mmol/1) clamps. RESULTS Obese and lean NIDDM subjects demonstrated similar basal rates of glucose uptake (GU) (1.15 ± 0.08 vs. 1.26 ± 0.08 mmol/min, NS) as well as oxidative (0.49 ± 0.07 vs. 0.53 ± 0.05 mmol/min, NS) and nonoxidative (0.67 ± 0.10 vs. 0.73 ± 0.12 mmol/min, NS) glucose metabolism. During hyperinsuhnemic glucose clamp studies, rates of GU were lower in obese NIDDM subjects (34.1 ± 2.3 vs. 55.2 ± 3.8 μmol · kg fat-free mass [FFM] -1 · min -1 , P ≥ 0.001) as were rates of oxidative (14.1 ± 1.3 vs. 22.1 ± 2.1 μmol · kg FFM -1 · min -1 P -1 · min -1 P ox ) and nonoxidative glucose metabolism (N ox ) was comparable in both groups (G ox 42% in obese and 41% in lean subjects; N ox 58% in obese and 59% in lean subjects). The NIDDM groups had similar basal free fatty acid levels that were suppressed equally during hyperinsulinemic clamps. However, basal fat oxidation (F ox ) was greater in the obese NIDDM group (103 ± 11 vs. 73 ± 8 μmol/min, P ≥ 0.05) and was less suppressed to insulin (74 ± 13 vs. 16 ± 3 μmol/ min, P CONCLUSIONS These results indicate that when obesity is present in NIDDM subjects with this degree of hyperglycemia, insulin-stimulated GU is lower by 35-40%. Reduced GU in obese NIDDM subjects leads to decreased intracellular substrate availability and lower rates of oxidative and nonoxidative glucose metabolism. Insulin suppression of F ox is also impaired when obesity is present and may contribute to decreased insulin-mediated GU in NIDDM. We conclude that obesity increases insulin resistance in NIDDM primarily by effects on GU rather than the intracellular pathways of glucose metabolism.

Contribution of Obesity to Defects of Intracellular Glucose Metabolism in NIDDM

and anaplerosis in heart: validation with syntactic model

To determine the dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus (NIDDM), indirect calorimetry was performed on eight matched control and NIDDM subjects during the basal state and during three glucose clamps at insulin infusion rates of 150, 300, and 1,500 pmol.m-2.min-1. Hyperglycemia was used to achieve matched rates of glucose uptake at each insulin infusion. Glucose uptake in the basal state was greater in NIDDM [3.75 +/- 0.23 vs. 2.50 +/- 0.10 mg.kg fat-free mass (FFM)-1.min-1, P less than 0.005] but was similar at approximately 8, 12, and 26 mg.kg FFM-1.min-1 at each insulin infusion. Basal protein oxidation, fat oxidation, and plasma free fatty acids were similar and equally sensitive to suppression by insulin in both groups. Glucose oxidation was reduced 20-26%, and circulating lactate increased 50-90% at physiological but not at pharmacological insulin concentrations in NIDDM. The dose-response relationship between serum insulin and glucose oxidation was right shifted in NIDDM with half-maximal activation at 368 +/- 91 vs. 179 +/- 27 pM in controls (P less than 0.05). In conclusion, glucose oxidation is reduced at physiological insulin concentrations in NIDDM and cannot be explained by concomitant obesity, increased fat oxidation, or reduced glucose uptake but results from impaired sensitivity to stimulation by insulin, possibly at pyruvate dehydrogenase.

Dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus.

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Dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus.