Islet transplantation found to restore glucose counterregulation

CHIGAGO – Intrahepatic islet transplantation restored glucose counterregulation and improved hypoglycemia symptoms in patients with longstanding type 1 diabetes, results from a small single-center study showed.

The findings support the consideration of the procedure in patients with severe hypoglycemia unawareness, Dr. Michael R. Rickels reported at the annual scientific sessions of the American Diabetes Association.

Currently, islet transplantation is being evaluated as a potential treatment for patients with type 1 diabetes experiencing severe problems with hypoglycemia," Dr. Rickels of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, said in an interview. "Difficulty with hypoglycemia increases with longer duration of type 1 diabetes as physiologic defense mechanisms against the development of low blood glucose fail. This study documents absent glucose production by the body during hypoglycemia in patients with longstanding type 1 diabetes that is restored 6 months after undergoing islet transplantation."

In an effort to determine the effect of intrahepatic islet transplantation on glucose counterregulation and hypoglycemia symptoms in patients with longstanding type 1 diabetes Dr. Rickels and his associates evaluated 20 subjects who underwent hyperinsulinemic, hypoglycemic, and euglycemic clamps with infusion of the tracer 6,6-²H₂ glucose for measurement of endogenous glucose production. Of the 20 study participants, 12 had longstanding type 1 diabetes (average of 29 years) and underwent intrahepatic islet cell transplantation, and 8 were normal controls. The mean duration of type 1 diabetes in the patients was 29 years, their mean Clarke score was 6.3, and their mean HYPO score was 2,564, indicating hypoglycemia unawareness and severe problems with hypoglycemia.

The patients received a mean of 9,648 islet equivalents/kg by portal vein infusion. As a result 10 of 12 (83%) achieved insulin independence and their hemoglobin A_1c levels dropped from a mean of 7.1 to a mean of 5.6 (P less than .001). They also experienced amelioration of hypoglycemia.

For the 12 patients with type 1 diabetes and 6 normal controls, during the final hour of the 4-hour hypoglycemic clamp, the mean level of plasma glucagon was 33 pg/mL in patients prior to islet transplantation, 60 pg/mL in patients after islet transplantation, and about 90 pg/mL in normal controls (P less than .001 for both vs. prior to islet transplantation).

Similar associations were observed for other measurements. The mean level of epinephrine was 116 pg/mL in patients prior to islet transplantation, 253 pg/mL in patients after islet transplantation, and 380 pg/mL in normal controls (P less than .01 for both vs. prior to islet transplantation and normal controls vs. after islet transplantation). The mean level of free fatty acids was 50 mcM in patients prior to islet transplantation, 161 mcM in patients after islet transplantation, and 95 mcM in normal controls (P less than .05 for both vs. prior to islet transplantation). The mean level of endogenous glucose production was 0.6 mg/kg per min in patients prior to islet transplantation, 1.2 mg/kg per min in patients after islet transplantation, and 1.4 mg/kg per min in normal controls (P less than .01 for both vs. prior to islet transplantation).

"These results indicate that present patient selection criteria developed by the Clinical Islet Transplantation Consortium for the protocols in which the current study’s patients participated indeed identify individuals with absent glucose counterregulation, and with the recovery of glucose counterregulation post transplant supports the consideration of islet transplantation as a potential treatment for patients with type 1 diabetes experiencing the most problems with hypoglycemia," said Dr. Rickels, who is also medical director for the hospital’s pancreatic islet cell transplantation program.

He noted certain limitations of the study, including the fact that it was "a small mechanistic study conducted in 12 patients at the University of Pennsylvania, so the results may not be generalizable to the larger population of type 1 diabetes patients who may undergo islet transplantation."

The study was supported by funding from the National Institutes of Health. Dr. Rickels said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

CHIGAGO – Intrahepatic islet transplantation restored glucose counterregulation and improved hypoglycemia symptoms in patients with longstanding type 1 diabetes, results from a small single-center study showed.

The findings support the consideration of the procedure in patients with severe hypoglycemia unawareness, Dr. Michael R. Rickels reported at the annual scientific sessions of the American Diabetes Association.

Currently, islet transplantation is being evaluated as a potential treatment for patients with type 1 diabetes experiencing severe problems with hypoglycemia," Dr. Rickels of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, said in an interview. "Difficulty with hypoglycemia increases with longer duration of type 1 diabetes as physiologic defense mechanisms against the development of low blood glucose fail. This study documents absent glucose production by the body during hypoglycemia in patients with longstanding type 1 diabetes that is restored 6 months after undergoing islet transplantation."

In an effort to determine the effect of intrahepatic islet transplantation on glucose counterregulation and hypoglycemia symptoms in patients with longstanding type 1 diabetes Dr. Rickels and his associates evaluated 20 subjects who underwent hyperinsulinemic, hypoglycemic, and euglycemic clamps with infusion of the tracer 6,6-²H₂ glucose for measurement of endogenous glucose production. Of the 20 study participants, 12 had longstanding type 1 diabetes (average of 29 years) and underwent intrahepatic islet cell transplantation, and 8 were normal controls. The mean duration of type 1 diabetes in the patients was 29 years, their mean Clarke score was 6.3, and their mean HYPO score was 2,564, indicating hypoglycemia unawareness and severe problems with hypoglycemia.

The patients received a mean of 9,648 islet equivalents/kg by portal vein infusion. As a result 10 of 12 (83%) achieved insulin independence and their hemoglobin A_1c levels dropped from a mean of 7.1 to a mean of 5.6 (P less than .001). They also experienced amelioration of hypoglycemia.

For the 12 patients with type 1 diabetes and 6 normal controls, during the final hour of the 4-hour hypoglycemic clamp, the mean level of plasma glucagon was 33 pg/mL in patients prior to islet transplantation, 60 pg/mL in patients after islet transplantation, and about 90 pg/mL in normal controls (P less than .001 for both vs. prior to islet transplantation).

Similar associations were observed for other measurements. The mean level of epinephrine was 116 pg/mL in patients prior to islet transplantation, 253 pg/mL in patients after islet transplantation, and 380 pg/mL in normal controls (P less than .01 for both vs. prior to islet transplantation and normal controls vs. after islet transplantation). The mean level of free fatty acids was 50 mcM in patients prior to islet transplantation, 161 mcM in patients after islet transplantation, and 95 mcM in normal controls (P less than .05 for both vs. prior to islet transplantation). The mean level of endogenous glucose production was 0.6 mg/kg per min in patients prior to islet transplantation, 1.2 mg/kg per min in patients after islet transplantation, and 1.4 mg/kg per min in normal controls (P less than .01 for both vs. prior to islet transplantation).

"These results indicate that present patient selection criteria developed by the Clinical Islet Transplantation Consortium for the protocols in which the current study’s patients participated indeed identify individuals with absent glucose counterregulation, and with the recovery of glucose counterregulation post transplant supports the consideration of islet transplantation as a potential treatment for patients with type 1 diabetes experiencing the most problems with hypoglycemia," said Dr. Rickels, who is also medical director for the hospital’s pancreatic islet cell transplantation program.

He noted certain limitations of the study, including the fact that it was "a small mechanistic study conducted in 12 patients at the University of Pennsylvania, so the results may not be generalizable to the larger population of type 1 diabetes patients who may undergo islet transplantation."

The study was supported by funding from the National Institutes of Health. Dr. Rickels said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

CHIGAGO – Intrahepatic islet transplantation restored glucose counterregulation and improved hypoglycemia symptoms in patients with longstanding type 1 diabetes, results from a small single-center study showed.

The findings support the consideration of the procedure in patients with severe hypoglycemia unawareness, Dr. Michael R. Rickels reported at the annual scientific sessions of the American Diabetes Association.

Currently, islet transplantation is being evaluated as a potential treatment for patients with type 1 diabetes experiencing severe problems with hypoglycemia," Dr. Rickels of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, said in an interview. "Difficulty with hypoglycemia increases with longer duration of type 1 diabetes as physiologic defense mechanisms against the development of low blood glucose fail. This study documents absent glucose production by the body during hypoglycemia in patients with longstanding type 1 diabetes that is restored 6 months after undergoing islet transplantation."

In an effort to determine the effect of intrahepatic islet transplantation on glucose counterregulation and hypoglycemia symptoms in patients with longstanding type 1 diabetes Dr. Rickels and his associates evaluated 20 subjects who underwent hyperinsulinemic, hypoglycemic, and euglycemic clamps with infusion of the tracer 6,6-²H₂ glucose for measurement of endogenous glucose production. Of the 20 study participants, 12 had longstanding type 1 diabetes (average of 29 years) and underwent intrahepatic islet cell transplantation, and 8 were normal controls. The mean duration of type 1 diabetes in the patients was 29 years, their mean Clarke score was 6.3, and their mean HYPO score was 2,564, indicating hypoglycemia unawareness and severe problems with hypoglycemia.

The patients received a mean of 9,648 islet equivalents/kg by portal vein infusion. As a result 10 of 12 (83%) achieved insulin independence and their hemoglobin A_1c levels dropped from a mean of 7.1 to a mean of 5.6 (P less than .001). They also experienced amelioration of hypoglycemia.

For the 12 patients with type 1 diabetes and 6 normal controls, during the final hour of the 4-hour hypoglycemic clamp, the mean level of plasma glucagon was 33 pg/mL in patients prior to islet transplantation, 60 pg/mL in patients after islet transplantation, and about 90 pg/mL in normal controls (P less than .001 for both vs. prior to islet transplantation).

Similar associations were observed for other measurements. The mean level of epinephrine was 116 pg/mL in patients prior to islet transplantation, 253 pg/mL in patients after islet transplantation, and 380 pg/mL in normal controls (P less than .01 for both vs. prior to islet transplantation and normal controls vs. after islet transplantation). The mean level of free fatty acids was 50 mcM in patients prior to islet transplantation, 161 mcM in patients after islet transplantation, and 95 mcM in normal controls (P less than .05 for both vs. prior to islet transplantation). The mean level of endogenous glucose production was 0.6 mg/kg per min in patients prior to islet transplantation, 1.2 mg/kg per min in patients after islet transplantation, and 1.4 mg/kg per min in normal controls (P less than .01 for both vs. prior to islet transplantation).

"These results indicate that present patient selection criteria developed by the Clinical Islet Transplantation Consortium for the protocols in which the current study’s patients participated indeed identify individuals with absent glucose counterregulation, and with the recovery of glucose counterregulation post transplant supports the consideration of islet transplantation as a potential treatment for patients with type 1 diabetes experiencing the most problems with hypoglycemia," said Dr. Rickels, who is also medical director for the hospital’s pancreatic islet cell transplantation program.

He noted certain limitations of the study, including the fact that it was "a small mechanistic study conducted in 12 patients at the University of Pennsylvania, so the results may not be generalizable to the larger population of type 1 diabetes patients who may undergo islet transplantation."

The study was supported by funding from the National Institutes of Health. Dr. Rickels said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com