No abstract

In patients with type 2 diabetes, gastric inhibitory polypeptide (GIP) has lost much of its insulinotropic activity. Whether this is similar in first-degree relatives of patients with type 2 diabetes is unknown. A total of 21 first-degree relatives, 10 patients with type 2 diabetes, and 10 control subjects (normal oral glucose tolerance) were examined. During a hyperglycemic "clamp" (140 mg/dl for 120 min), synthetic human GIP (2 pmol ⅐ kg ؊1 ⅐ min ؊1 ) was infused intravenously (30 -90 min). With exogenous GIP, patients with type 2 diabetes responded with a lower increment (⌬) in insulin (P ‫؍‬ 0.0003) and C-peptide concentrations (P < 0.0001) than control subjects. The GIP effects in first-degree relatives were diminished compared with control subjects (⌬ insulin: P ‫؍‬ 0.04; ⌬ C-peptide: P ‫؍‬ 0.016) but significantly higher than in patients with type 2 diabetes (P < 0.05). The responses over the time course were below the 95% CI derived from control subjects in 7 (insulin) and 11 (C-peptide) of 21 first-degree relatives of patients with type 2 diabetes. In conclusion, a reduced insulinotropic activity of GIP is typical for a substantial subgroup of normoglycemic first-degree relatives of patients with type 2 diabetes, pointing to an early, possibly genetic defect.

Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S I ), and pancreatic ␤-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n ‫؍‬ 10), RIS (5 mg/day; n ‫؍‬ 10), or gelatin capsules (n ‫؍‬ 6) for 4 -6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (؉91 ؎ 20%; P ‫؍‬ 0.000001) reflecting marked increases in subcutaneous (؉106 ؎ 24%; P ‫؍‬ 0.0001) and visceral (؉84 ؎ 22%; P ‫؍‬ T he introduction of atypical antipsychotics in psychopharmacology represented a major advance in the treatment of schizophrenia, providing an effective therapy for both positive and negative symptoms of psychosis while minimizing the extrapyramidal effects characteristic of earlier therapeutic options. Indeed, these medications are widely prescribed (ϳ3% of the U.S. population) for treatment of schizophrenia, as well as bipolar disorder, depression, and dementia.In the face of their widespread use, concern has arisen regarding treatment-associated weight gain and apparent increased diabetes risk (1-3). It is unclear whether weight gain is a direct effect of the drug or secondary to behavioral changes, such as increased sedation associated with pharmacotherapy. But regardless of its causality, obesity is a significant public health concern and is a well-documented risk factor for type 2 diabetes as well as other chronic diseases, such as cancer and atherosclerosis (4 -6). Nonetheless, diabetes risk with antipsychotic use has also been reported in the absence of significant weight gain (7-9).Evidence linking atypical antipsychotics to metabolic dysregulation is largely based on case reports and retrospective analyses, which note a disproportionately greater number of patients developing fasting hyperglycemia and new-onset diabetes or exhibiting exacerbation of preexisting diabetes soon after the initiation of atypical antipsychotic treatment (10 -15). Henderson et al. (14) reported that Ͼ30% of schizophrenic patients receiving clozapine developed diabetes within a 5-year follow-up, and those with preexisting diabetes required increased insulin dosing. Federal Drug Administration reports (10), based in part on the Medwatch Surveillance Program, provide further evidence of the excessive occurrence of new-onset diabetes and exacerbation of preexisting disease with clozapine compared with disease incidence in untreated individuals. More recently, olanzapine (OLZ) and risperidone (RIS), which collectively account for Ͼ80% of all drugs prescribed of their class of atypical antipsychotics, have also been associated with metabolic abnormalities, though OLZ is generally linked to greater relative risk for diabetes (11,16) and more marked obesity (3,11,17) compared with RIS (12,13,18).It is indeed challenging to study the actions of antipsy-