The Aging Endocrine Pancreas: Characterization of the Entero-insular Axis Physiology in the Elderly

• Homeostasis Model Assessment Insulin Resistance (HOMA-IR) Index [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: No ]
  Insulin sensitivity index calculated as HOMA-IR = (Glucose * Insulin) / 22.5, where glucose is mmol/L and insulin is mili-units (mU)/L. Higher values indicate lower insulin sensitivity.
• Glucose Infusion Rate [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: No ]
  Whole-body insulin sensitivity, as estimated by the mean glucose infusion rate corrected for fat-free mass(FFM){mg*[kg(FFM)^-1]*min*10} at last 60 min of 180-min hyperglycemic clamp
• Adaptive Beta-cell Insulin Production. The Product of Meal Tolerance Test-derived Insulinogenic Index (IGI) for Clamp-derived Insulin Sensitivity Index (ISI) in Normoglycemic Subjects After 65 Years Old in Comparison With Middle-age Normoglycemic Subjects [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: Yes ]
  Beta-cell function was determinated as the beta-cell secretion measured by meal tolerance test adjusted by insulin sensitivity assessed by the hyperglycemic clamp test:Insulinogenic Index/Insulin Sensitivity Index adjusted by free fat mass
• Distinctive Beta-cell Function From the Arginine Stimulation Test in Normoglycemic Subjects After Sixty-five Years Old in Comparison With Middle-age Normoglycemic Subjects. [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: Yes ]
  Distinctive beta-cell function as measured by the disposition index - based on the acute insulin response from the arginine stimulation test versus glucose infusion rate adjusted by free fat mass from hyperglycemic clamp - in normoglycemic subjects after sixty-five years old in comparison with middle-age normoglycemic subjects.

• Serum Dipeptidyl Peptidase IV (DPP-IV) Concentration [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: Yes ]
  measured in fasting serum sample by ELISA kit
• GLP-1 Area Under the Curve (AUC) [ Time Frame: 1 month from screening visit ] [ Designated as safety issue: Yes ]
  Area under the curve of glucagon-like peptide (GLP-1) concentrations (measured by ELISA kit) from time 0 to 180 min during a standard meal tolerance test, calculated by the trapezoidal rule.

• Distinctive whole-body insulin sensitivity, as estimated by hyperglycemic clamp in normoglycemic subjects after sixty-five years old in comparison with middle-age normoglycemic subjects. [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: No ]
• Distinctive beta-cell function (beta-cell secretion and sensitivity), as measured by hyperglycemic clamp in normoglycemic subjects after sixty-five years old in comparison with middle-age normoglycemic subjects. [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: No ]
• Distinctive acute insulin response as measured by arginine stimulation test in normoglycemic subjects after sixty-five years old in comparison with middle-age normoglycemic subjects. [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: No ]
• Distinctive DPP-IV activity as measured by spectrophotometer in normoglycemic subjects after sixty-five years old in comparison with middle-age normoglycemic subjects. [ Time Frame: within 1 month from screening visit ] [ Designated as safety issue: No ]

Like most endocrine axes, the entero-insular axis is expected to go through an age-related physiological deterioration, what might contribute to special features of the elderly onset type 2 diabetes in comparison to middle-age.

Twenty four NGT volunteers will be evaluated by a meal tolerance test (MTT) for incretin hormone measurements, and by the hyperglycemic clamp followed by an arginine test for assessing the beta-cell function and the acute insulin response. Others parameters as body composition and basic biochemistry will be also evaluated at Laboratory of Investigation on Metabolism and Diabetes - LIMED / State university of Campinas, Brazil.

The characterization of the glucagon-like peptide-1 (GLP-1) production, dipeptidyl peptidase IV (DPP-IV) activity and/or endocrine pancreas incretin-response at aging, might be an interesting evidence to reinforce an incretin-based therapeutic approach for elderly onset type 2 diabetes.

Adult normoglycemic subjects

• Diabetes Mellitus, Type 2
• Insulin Resistance

• Elderly NGT
  Normoglycemic subjects 65-80 years old
• Middle-age NGT
  Middle-age normoglycemic subjects 35 to 50 years old.

Inclusion Criteria:

• Stable weight (< 5% variation) within the last three months
• Age: 35 to 50 years old for middle-age group, and 65 to 80 years old for elderly group.
• BMI: 20 to 29.9 kg/m2
• Normal glucose tolerance (NGT) for groups Elderly and Middle-age

Exclusion Criteria:

• Use of estrogen, progestogen or systemic corticosteroids.
• Hepatic cirrhosis, renal failure or any clinical condition with impaired insulin sensitivity
• Smoking
• Obesity
• Uncontrolled systemic or debilitating diseases