Glycemic treatment: Control of glycemia.

This is the first of three articles dealing with the International Diabetes Federation meeting, which was held in Paris, 24–29 August 2003. Michael Stumvoll (Tübigen, Germany) gave the Minkowski lecture, discussing aspects of the control of glycemia, illustrating the “hyperbolic law of glucose control,” depicting the inverse relationship between insulin secretion and insulin sensitivity. If one adds the 2-h glucose in a threedimensional plot, however, as insulin resistance worsens there is a progressive increase in the 2-h glucose, so that one cannot consider insulin secretion to perfectly balance the degree of insulin resistance (1). Stumvoll gave an overview of the fascinating science involved in understanding glycemia, describing the products of six genes involved in glucose homeostasis. Adiponectin is a protein released by fat cells to an extent inversely related to total body fat mass. Treatment of insulin-resistant diabetic mice with adiponectin decreases glucose levels, and in humans there is an inverse relationship between the degree of insulin resistance and the adiponectin level. Stearoyl-CoA desaturase regulates tissue lipid synthesis and is involved in the metabolism of stearate to oleate. In liver, inhibition of this enzyme prevents hepatic steatosis in leptin-deficient animals, and the oleate-tostearate ratio on liver biopsy is inversely related to the insulin sensitivity. The insulin receptor (IR) substrate (IRS)1 modulates insulin secretion, with -cell overexpression of normal IRS1 increasing insulin secretion, whereas overexpression of an abnormal IRS1 decreases insulin secretion by these cells. In humans, those with the Gly972Arg IRS1 polymorphism have shown a decrease in both the firstand second-phase insulin secretory response to intravenous glucose (2). CEACAM1 (CEA-related cell adhesion molecule 1) regulates a pathway responsible for IR internalization, and abnormality causes diabetes. CEACAM1 causes receptor-mediated hepatic insulin endocytosis and degradation in a phosphorylation-dependent manner (3). The liver clears approximately half of the insulin molecules with each circulatory passage, a phenomenon negatively associated with free fatty acid (FFA) levels. Peroxisome proliferator–activated receptor (PPAR) 2 is involved in transcriptional regulation of a host of processes. The Pro12Ala polymorphism affects insulin clearance, which is greatest with Ala/Ala homozygotes, which show the greatest insulininduced suppression of lipolysis, further suggesting that release of fatty acids from adipose tissue modulates hepatic insulin degradation. The final gene product Stumvoll discussed is the IR, which has fascinating effects in the central nervous system. Mice that selectively do not express the IR in the central nervous system have evidence of overall insulin resistance. Using magnetoencephalography, it is possible to detect insulin effects in the human cerebral cortex during a hyperinsulinemic clamp, with specific analysis of the auditory cortex showing insulin action on the response to sound and attenuation of this response in persons with obesity. Type 2 diabetes treatment At a symposium sponsored by the U.K. Prospective Diabetes Study (UKPDS), Bernard Zinman (Toronto, Canada) discussed the baseline findings of the ADOPT (A Diabetes Outcome Prospective Trial) study of 4,356 persons randomized from type 2 diabetes diagnosis to glyburide, rosiglitazone, and metformin treatment. The mean glucose at onset was 150 mg/dl, 80% had metabolic syndrome, which was either diagnosed based on the Adult Treatment Panel III or World Health Organization criteria, and patients from North America were somewhat younger and more obese. Of the subjects, 4.2% were GAD positive and similar in most measures to those who were negative, although with somewhat higher triglyceride and lower HDL, lower fasting insulin, and higher initial glucose, suggesting a greater degree of -cell dysfunction, although similar when corrected for the degree of insulin sensitivity. Microalbuminuria was high in prevalence and associated with obesity and higher glucose and blood pressure levels. A number of presentations at the meeting addressed additional baseline findings. Zinman et al. (abstract 417) compared the 170 persons positive for GAD antibody with the 3,896 GAD-negative persons, reporting that the HbA1c was 7.5 vs. 7.3%, with the former showing somewhat lower fasting and glucose-stimulated insulin, higher HDL cholesterol, and lower triglyceride levels, which is compatible with having a lesser degree of insulin resistance and features of type 1 diabetes. Viberti et al. (abstract 945) analyzed characteristics of the subjects with microalbuminuria (15.2%) in the cohort, showing 63 vs. 57% male sex and greater waist circumference (109 vs. 105 cm) and BMI (33 vs. 32 kg/m). The microalbuminuric persons had higher fasting glucose, HbA1c, and blood pressure, and the urine microalbumin correlated with homeostasis model assessment of insulin resistance, Creactive protein, fibrinogen, and white blood cell count. Rury Holman (Oxford, U.K.) presented new results from the UKPDS (see ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●